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I i ' 




Environmental Protection 
Agency 


I icjaiii I CiitJULd 

Research Laboratory 
Research Triangle Park 
NC 27711 


tKA-ouu/ a- /»-uua 
May 1978 



Research and Development 


»EPA 


Methodologies and Protocols 
in Clinical Research- 












































































































































































































DISCLAIMER 

This report has been reviewed by the Health Effects 
Research Laboratory, U.S. Environmental Protection 
Agency, and approved for publication. Mention of 
trade names or commercial products does not consti¬ 
tute endorsement or recommendation for use. 


EPA-600/9-78-008 


Methodologies and Protocols 
in Clinical Research: 
Evaluating Environmental 
Effects in Man 

Symposium Proceedings 

May 1978 


United States Environmental Protection Agency 

Health Effects Research Laboratory 

Clinical Studies Division 

Research Triangle Park, North Carolina 27711 


,A1if7 



ni 

LO 

ca 


Preface 


The relative affluence of the industrial age has been attain¬ 
ed at the cost of degrading the quality of some aspects of life. 
Conditions of the sort described by Dickens have, in large measure, 
been corrected. But there remains the pervasive and insidious danger 
of man's increasing ability to alter his environment. In the final 
analysis, mankind is concerned with the repercussions of environ¬ 
mental changes on his health and happiness. Both of these quali¬ 
ties are very difficult to measure in a quantitative way. This 
symposium, however, addresses some aspects of the quantitative 
assessment of health status. 

In some respects, the proper study of environmental influence 
on human health is the study of humans whose environment is altered 
in a controlled way. The methodologic, ethical, legal, and social 
aspects of such research are the major topics of this symposium. 
Because of the inherent problems and restrictions in these major 
topics, there are many environmental health questions that will 
always remain beyond the p\irview of clinical research. Because of 
the unique advantages of clinical research, there are some environ¬ 
mental health questions that are answered best by clinical research. 
One of the objectives of this symposium is to formulate criteria 
for identifying which kinds of environmental health questions are 
particularly suited to the clinical research approach and which 
definitely are not. i 

The levels of sophistication involved in most aspects of clini¬ 
cal environmental research is increasing rapidly. Those who are 
relatively new to this field may assume that space age technology 
rsflects the recent advent of this kind of research. This is not 


III 


true. Modern clinical environmental research draws on a rich 
heritage of simple, elegant studies that have provided the foun¬ 
dation of human stress physiology. I hope we are successful in 
using the tools of modern technology in responding to the needs of 
modern society. To accomplish this, we must continue to perform 
well in the tradition of those whose work has made ours possible 
so that we can improve the quality of life for those who follow 
us on this planet. 


John H. Knelson, M.D. 
Clinical Studdies Division 


IV 


Contents 


PART ONE - PHILOSOPHY OF CLINICAL RESEARCH 

Ethical Considerations in Research 
Involving H\iman Subjects, 

Harmon L. Smith . 3 

Discussion Summary . 17 

Legal Aspects of Using Human Subjects 
in Environmental Research, 

Michael V. Mclntire.. 

Discussion Siammary.29 

Informed Consent — Its Function 
and Limitations, 

Charles E. Daye.. 

Discussion Summary . 49 

Role and Function of Committees on 
Protection of Human Subjects in Research, 

Edward Bishop . 51 

Discussion Summary . 59 


V 










PART TWO — METHODOLOGIES AND PROTOCOLS IN ENVIRONMENTAL 
CLINICAL RESEARCH 

Developing Methodologies — Environmental Studies, 

Steven Horvath . 63 

Discussion Summary . 69 

Rationale for Experimental Design, 

John H. Knelson.71 

Discussion Summary . 79 

Subject Selection, Investigator Interactions, 

Informed Consent in Clinical and 
Environmental Research, 

David A. Otto and Jeanne T. Hernandez.81 

Discussion Summary . 91 

Acute Versus Chronic Studies, 

David Bates.93 

Discussion S\immary.101 

Sensitive Populations in Environmental 
Studies, 

Carl Shy* 

Role of Automatic Data Processing in 
Clinical Research, 

Frank Starmer.103 

Discussion Summary . 109 

PART THREE - ENVIRONMENTAL AND PHYSICAL SAFETY 

CONSIDERATIONS IN HUMAN EXPOSURE FACILITIES 

Environmental Controls and Safeguards, 

Morton Lippmann . 113 

Discussion Summary . 131 

Electrical Surveillance and Integrity, 

G. Guy Knickerbocker... 

♦Paper not available at time of publication. 


VI 
















Discussion Summary 


145 


PART FOUR - EPA HUMAN STUDIES PROGRAMS 


CLEANS/CLEVER System Approach, 

John H. Knelson.149 

PART FIVE - SPECIAL CONSIDERATIONS AND APPROACHES 

IN ENVIRONMENTAL CLINICAL RESEARCH 

Introduction to Panel Discussion, 

Philip Bromberg . 161 

Statement, Robert Frank . 165 

Discussion.171 

Statement, Bernard E. Statland . 175 

Discussion.191 

Statement, L. David Pengelly . 199 

Discussion.203 

Statement, Mario C. Battigelli . 209 

Discussion.213 

Appendix 

Program Participants . 223 


VII 














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PHILOSOPHY OF CLINICAL RESEARCH 


Moderator: Milan Hazucha, M.D. 








Ethical Considerations in Research 
Involving Human Subjects 

Harmon L Smith, Ph.D. 

Divinity School 
Duke University 


There is, I dare to think, broader consensus among physicians 
and ethicists on the meaning of "clinical research" than on "ethi¬ 
cal issues," so I want to introduce these observations on ethical 
issues in clinical research by commenting on what constitutes an 
ethical issue. No doubt, you have noticed that the words "ethics" 
and "morals" are heir to many interpretations; indeed, they are 
frequently employed as synonyms in medical literature. Therefore, 
my initial focus will be to discriminate between these terms. 

ETHICS AND MORALS 

In the history of Western philosophical and theological re¬ 
flection, ethics (or moral philosophy) is typically characterized 
by a spirit of radical inquiry; it does not attempt to supply so¬ 
lutions for moral dilemmas, but it does undertake to provide a ra¬ 
tional framework for comprehending the complexities of moral judg¬ 
ment. Put simply, the moral question is a "what" question—what 
ought I do, what good should I seek, what is the right action in 
this situation, what end should I pursue? Correspondingly, the 
ethical question is a "why" question—why should I do this, why 
do I seek this good action rather than some other action, why is 
this action right or appropriate? 

In other words, ethical questions attempt to reference action 


3 



to an affirmative warrant, they ask whether there is a proper rea¬ 
son for making a particular choice, and whether there is coherence 
and congruency between what one believes and how one behaves. On 
these terms, a moral action is one that expresses an antecedent 
value commitment. 

In this classic study of American racism, Gunnar Myrdal argues 
that the roots of American racism lie in a contradiction between 
American political and social ideology. In his book. An American 
Dilemma , Myrdal shows that racism is the product of a distancing, 
a gap, a discontinuity between the "American creed" and the "Amer¬ 
ican deed." The "creed" declares that all persons are created 
equal; the "deed" treats some persons as superior and others as 
inferior. The Biblical word for this disparity is hypocrisy (from 
the Greek hypokrisis , literally, to act a part, to pretend to be 
what one is not), and immorality is the name we give to conduct 
that is contradictory of, or in conflict with, character. Thus, 
one useful reason for distinguishing ethics from morals is to 
undertake a rational analysis of the value predicates of actions 
and to test their expression in behavior. 

DESCRIPTIVE/PRESCRIPTIVE ANALYSIS 

The analysis of the value predicates of action and their ex¬ 
pression in behavior is principally of two sorts: descriptive and 
prescriptive, or operational and normative. In descriptive analy¬ 
sis, the values that appear to be informing action are inferred 
from the actual conduct of individuals or groups. Thus, if a per¬ 
son or group steals, it is not unreasonable to suppose that (at 
least in those situations in which stealing is practiced) there are 
no absolute property rights. It would appear further that property 
(at least the property in this situation) appropriately belongs to 
whoever can possess it, by fair means or foul. Conversely, if a 
person or group does not steal, it is reasonable to suppose that 
the mores of this group prohibit it and, moreover, that property 
is somehow thought to be inviolate. Descriptive analysis identifies 
the ethics of persons or groups inductively from observation of 
actual conduct. 

On the other hand, prescriptive or normative analysis takes 
its cue from an articulated system of values—usually a formal 
statement that affirms what is true, beautiful, and good—to ask 
two kinds of questions: (1) In view of a given statement of what 
is valuable, what actions are derivatively appropriate? If this 
statement represents what we believe, how ought we to behave? (2) 
Given a statement of what is valuable, are the actions we observe 
appropriate? Are these modes of conduct coherent with this charac¬ 
ter, are these actions congruent with these affirmations? 


4 






I tell itiy classes about the case of an avowed and apparently 
devout cannibal who is a practicing vegetarian! Descriptive analy¬ 
sis says simply that this is an immoral person—he does not prac¬ 
tice what he preaches^ there is no congruency or coherence between 
what he affirms and how he acts. Prescriptive analysis, on the 
other hand, is more concerned with the predicates of the cannibal's 
behavior; that is, whether cannibalism qua cannibalism is an appro¬ 
priate or right or good philosophy. Depending on the answer to 
this question, prescriptive analysis will tend to make one of two 
judgments—either that cannibalism is a licit philosophy, in which 
case, this "vegetarian cannibal" is confused or cannot be responsi¬ 
ble to his conviction and therefore is not a dependable moral agent; 
or that cannibalism is an illicit philosophy, and while this person 
may be doing the right thing, he's doing it for the wrong reason. 

In either case, a negative judgment is rendered in the absence of 
clarity and continuity between creed and deed. 

ETHICAL ISSUES AS MORAL DILEMMAS 

To speak about ethical issues in clinical research is to engage 
this same genre of questions and judgments. But in this context, 
our attention is drawn to physicians (and possibly others) who (a) 
are simultaneously acting under the governance of both personal and 
professional ethical sensibilities, which suggests that conflict 
may sometimes occur between these two, and who (b) are carrying out 
scientific investigations on patients who have presented themselves 
for care and treatment, which also suggests that a disturbance may 
be experienced, this time by patients who learn that they are ex¬ 
perimental subjects. In addition, physicians may find it difficult 
to reconcile their responsibilities as clinicians with their respon¬ 
sibilities as investigators. 

So, an "ethical issue" can be either or both of two sorts: it 
can be identified as an incongruence or discontinuity between 
affirmation and actions, or it can be identified as an inappropriate 
affirmation or a mistaken value system. In both instances, an 
"ethical issue" ordinarily presents as a moral dilemma. 

In today's society, the ethical issues in clinical research 
seem to be basically of the first sort, that is, as a tension or 
distancing between belief and behavior. As one reads the literature 
of clinical investigations—say, from Nuremberg to the present—it 
is evident that the principal ethical questions ask what research 
is appropriate under already established guidelines, and whether 
investigators are, in fact, honoring those principles in both proto¬ 
col and practice. Of course, innovations in therapy together with 
iosity generated out of previous studies constantly push against 
the boundaries of those principles, and occasionally, there is talk 


5 



about reformulating the goals and goods to which medicine is com¬ 
mitted. 

It has been suggested, for example, that cloning and cyborg- 
androids offer the prospect of larger and less restricted pools 
for "human" experimentation, and that we should move ahead with 
technologies in anticipation of the benefits that would result 
from their use. To cite only one instance: The care with which 
the current National Commission for the Protection of Human Sub¬ 
jects has proposed and promulgated guidelines for studies using 
abortuses, prisoners, the mentally infirm, and others as potentic^l 
research subjects makes it fair to say, I think, that there is a 
formal consensus in the U.S. concerning the values and obligations 
of clinical investigations. The ethical standards for clinical 
investigations appear to be settled if one takes these documents 
to be normative statements. 

THE ETHICS OF INVESTIGATION 

What are the standard values and obligations of the medical 
profession that govern clinical investigations? Their documentary 
expression can be found (among other places) in the Nuremberg Code,^ 
in the Declaration of Helsinki,** in the policies of DHEW regarding 
the protection of human subjects,^ and in the AMA's "Ethical Guide¬ 
lines for Clinical Investigation."® A careful reading and content 
analysis of these statements shows that their substantial points 
focus on two principal interests; the study and the subject. More¬ 
over, three constituent heads can be denominated under each of these 
two governing titles: the sections that comment on the nature of 
the study typically address its purpose, its design and conduct, 
and its results; and the sections that speak to the role of parti¬ 
cipants in the study accentuate the physician-patient relationship, 
consent, and risk. All of these sections together constitute, in 
this literature, the ethical issues appropriate to clinical investi¬ 
gations, at least as perceived by those who formulated these state¬ 
ments . 

Study Guidelines 

The purpose of clinical studies, according to the Nuremberg 
Code, "should be such as to yield fruitful results for the good of 
society, unprocurable by other methods or means of study, and not 
random or unnecessary in nature." In Helsinki, the World Medical 
Association declared that, "It is essential that the results of 
laboratory experiments be applied to human beings to further scien¬ 
tific knowledge and to help suffering humanity." The AMA guidelines 
for clinical investigation, adopted in 1966, endorse these same 
ethical principles. In sum, they seem to state that what initially 


6 




legitimates clinical research is the need to test experimental 
hypotheses on human subjects to extend scientific knowledge and to 
alleviate human suffering. 

In addition, this purpose must be acknowledged in the design 
and conduct of the study. "A physician may participate in clinical 
investigation," according to the AMA guidelines, "only to the ex¬ 
tent that his activities are a part of a systematic program com¬ 
petently designed, under accepted standards of scientific research, 
to produce data which is scientifically valid and significant." 
Moreover, both the Nuremberg and Helsinki statements insist that 
the research should be designed and based on animal experiments and 
the natural history of the disease, and conducted only by scienti¬ 
fically qualified persons from whom "the highest degree of skill 
and care should be required." The point of these admonitions is 
that a study must be ethical in its design and conduct if it 
intends to be ethical at all; that is, rather than judge the ethical 
aspects of a study solely on a post hoc basis, there are possibili¬ 
ties for ethical evaluation already present in a study's intention 
and methodology. 

Finally, these ethical guidelines hold that the results of the 
study should coinhere with its purpose. If the goal of clinical 
research is to test experimental hypotheses on human subjects to 
extend scientific knowledge and alleviate human suffering, the 
results of the investigation ought to show this. Sometimes con¬ 
structive advances in knowledge and innovative therapies are 
achieved, and sometimes it is discovered that the positive accom¬ 
plishment of a trial is to show that a given hypothesis is incorrect. 
In either case, the ethical burden is placed upon the investigator 
to show that the results of the study are in keeping with its 
purpose. 

The Subject's Rights 

The second principal interest that these documents address con¬ 
cerns the participants in clinical research and the two kinds of 
special consideration due them. Presuppositional to concerns for 
consent and risk is the physician-patient relationship . Without 
this, and without its being conceived in a certain way, there would 
be little or no point in going on to talk about consents and risks. 
The AMA guidelines state unambiguously that the investigator "should 
demonstrate the same concern and caution for the welfare, safety 
and comfort" of the experimental subject "as is required of a physi¬ 
cian who is furnishing medical care to a patient independently of 
any clinical investigations." The Declaration of Helsinki is, if 
anything, more rigorous: "The doctor can combine clinical research 

pj^ofessional care. . .only to the extent that clinical research 


7 










is justified by its therapeutic value for the patient" because 
"it is the duty of the doctor to remain the protector of the life 
and health of that person on whom clinical research is being 
carried out." 

These notions of subjects' rights and physicians' duties are 
reinforced in both the Nuremberg and Helsinki documents, with pro¬ 
visions for investigators to terminate, and subjects to withdraw 
from, experiments at any stage. What appears to be clearly at 
stake, and what is clearly affirmed in all these documents, is a 
sensitive and generous humanitarianism that imposes equally upon 
the investigator and the subject. Neither can treat or regard the 
other as merely a means to an end, because there is a fiduciary 
relationship between them, which is an inviolable end and which 
transcends the immediacy of any enterprise in which they may be 
jointly engaged. 

In this context, concerns for consent-getting and risk-assess ¬ 
ment make sense as logical extensions of the primary commitment to 
h\imanitarian ideals. Thus, the Nuremberg Code states that "voluntary 
consent of the human subject is absolutely essential," and the De¬ 
claration of Helsinki asserts categorically that "clinical research 
on a human being cannot be undertaken without his free consent, 
after he has been fully informed." 

Each of us could probably cite too many examples of the fail¬ 
ure to honor this fiduciary relationship. I recently experienced 
an especially poignant demonstration of this. I was on an airplane, 
comfortably settled into an aisle seat and reading an issue of The 
Lancet when, almost immediately after we were airborne, a woman 
who was sitting across the aisle leaned toward me and asked, "Are 
you a doctor?" "Yes," I said, "but probably not the kind you mean." 
"Then what kind of doctor are you?" she inquired. "A Ph.D., a 
doctor of philosophy." "Well," she said, "maybe you can help me 
anyhow." And then she proceeded to tell me her story. 

In early childhood her husband had received a diagnosis of 
"cerebral palsy"; in manhood he had experienced grand mal seizures; 
and now, more recently, he had undergone episodes of uncontrollable 
violent behavior during which he had hurt both himself and his wife. 
She was now returning home after having admitted her husband to a 
university medical center under the care of a neurosurgeon to whom 
she had been referred. She had seen this doctor, but their meeting 
had been very brief. 

Thereafter, she was contacted by one of the neurosurgeon's 
residents, and it was with him that she had a conversation about her 
husband s situation. She did not learn very much from that confer— 


8 







6nc6 becaus6/ she seid/ "He talked funny and I couldn't understand 
him." In response to my questions, it developed that the resident 
also had "different eyes." We concluded that he was probably not 
a native American. In any event, this woman did not understand 
what she was told by the resident. She had no opinion about fault¬ 
ing the young doctor for failing to communicate with her, and she 
turned aside my question about the neurosurgeon's responsibility 
to discuss her husband's case by saying that "he is so busy...he is 
very important and works very hard...lots of people like my hus¬ 
band depend on him...he's just too busy." 

This woman is a registered pharmacist, and I would have guessed 
her to be in her early thirties. She had signed the admissions 
forms and her plans were to return to the hospital in ten days, when 
her husband's initial work-up and perhaps other preliminary or 
exploratory procedures would be completed, to be present at the time 
of his surgery. She planned to return to the medical center in the 
early morning of the day when surgery was scheduled for noon; she 
did not know anything about any consent forms, but did know that 
she would be expected to sign some papers when she went back to 
the hospital. 

She could not describe what was going to be done to her husband 
over the next ten days, nor did she know what surgical procedure 
was scheduled at the end of that period. When I inquired whether 
her husband's treatments, whatever they were, would be directed to 
his cerebral palsy or his epilepsy, the wife's response was, "No, 
it's for his violence." "Well," I asked, "what surgery is going 
to be done?" "I don't know," she said, "but that's what I wanted 
to ask you about. I saw something about 'thalamus' and something 
about 'frontal.' Do you know what those mean?" I avoided answering 
that question, and asked whether she was satisfied with what she 
knew about her husband's treatment, and whether her questions to 
me indicated that she needed to know considerably more than she did. 
She acknowledged the force of both those questions, then added, I 
thought somewhat plaintively, "But they wouldn't hurt him, would 
they?" 


This was an uncomfortable conversation for me—uncomfortable for 
all the conventional reasons, to be sure; but more than that, it was 
uncomfortable because I am familiar with the symptoms she described 
and some aspects of the "innovative therapy" of "psychiatric neuro¬ 
surgery" being undertaken in that medical center for the control of 
violence. I did not want to alarm this woman, not only because I 
am not a medical doctor, but also because I did not have all the 
relevant facts before me. Nevertheless, I was disturbed by what I 
suspected was likely to happen to her husband, and my uneasiness was 
escalated by the knowledge that this woman and her husband lacked 


9 



the most rudimentary information and understanding of the husband's 
treatment. Without the necessary information and understanding, 
they could not participate significantly in the decision-making 
process. Preconditional to that, it was plain that the presumption 
of a convenantal bond, a fiduciary relationship between patient and 
physician, had been violated. 

By now the airplane was beginning its descent, and I wanted 
to let her know, without adding to her anxiety, that I thought 
the way her husband's case was being handled was very inappropriate 
and unsatisfactory. I suggested that she contact a local neuosur- 
geon, explain the situation, ask him to contact the medical center 
neurosurgeon on her behalf, and then have him explain to her her 
husband's treatment. I also suggested that she make arrangements 
to talk with the attending surgeon prior to surgery and before 
signing any further forms. Even with these suggestions, I felt 
frustrated and powerless. As she left the airplane, she expressed 
her disappointment that I would not or could not say any more than 
I had about what was likely to be in store for her husband. 

THE PATIENT'S CONSENT—^AN ETHICAL ISSUE OF THE 20TH CENTURY 

I find it interesting that, while the moral traditions of 
Western medicine contain provisions for a consent mechanism, the 
prominent role of consent as an explicit issue in medical ethics 
is a relatively recent one. In fact, there is no mention of con¬ 
sent in the Hippocratic Oath, or by Maimonides in the 12th century, 
or by other pre-19th century medical authorities. Indeed, there 
is no apparent concern among classical authorities for a special 
ethical obligation with respect to consent—and this is the case 
for both experimental and established therapies. 

The most persuasive explanation for this state of affairs is 
two-fold; (1) The beginning of human experimentation is typically 
identified with William Harvey's research in human circulation in 
the early 17th century (1628); however, the great commitments to 
research as a predominating direction of scientific medicine were 
not expressed until the mid-20th century. So, while there has 
always been curiosity in the clinical setting, it has only been in 
relatively recent times that clinical investigation has achieved 
such high priority and institutionalization. (2) Concurrently 
with this phenomenon of the socialization and politicization of 
medicine, an intellectual attitude developed in Western culture, 
which had as its primary objective the yielding of information 
through systematically designed experiments. This attitude, in 
turn, provoked conflict and competition with an older principle 
of primary patient benefit from medical intervention. 


10 




World War II, and the Nazi medical experiments in particular, 
exposed the weakness of experimental ethics that were based either 
solely or largely on social utility or scientific advance; and 
Nuremberg, although it focuses chiefly on experimentation, has 
become the landmark in the evolution of consent as a prominent 
issue in the ethics of health care. (I want to add, parenthetically, 
that the force of the Nuremberg Code is unquestionably directed 
toward the protection of patients and subjects, although it was 
propounded to guide physicians in carrying out studies on human 
subjects. In recent years, however, and in the wake of wide 
exposure of unethical studies and malpractice litigation, we are 
observing a subtle shift in the intention of consent-mechanisms 
from patient-subject protection to physician-investigator protec¬ 
tion. ) 

Since Nuremberg, four types of consent situations have been 
plainly identified: (1) the therapeutic setting, in which treatment 
is specifically and exclusively directed to the benefit of the pri¬ 
mary patient (e.g., appendectomy); (2) yet another therapeutic 
setting, but one in which the benefit of treatment is specifically 
and exclusively directed toward another recipient (e.g., tissue 
and/or organ transplantation involving a living donor); (3) the 
experimental setting, in which general or specific information is 
sought by procedures that are unrelated to a primary patient's 
(or subject's) care, but which may benefit others and/or increase 
medical knowledge (e.g., mass screenings for hypertension or trans¬ 
mission of hepatitis); and finally, (4) permutations or combinations 
of the preceding situations, in which a treatment of unknown efficacy 
and safety is administered both for possible benefit to patients 
(or subjects) and for potential extension of medical information 
(e.g., new chemotherapeutic agents for carcinoma). 

In all of these settings, the implementation of adequate con¬ 
sent-getting has been left primarily to physicians. Indeed, the 
Nuremberg Code states explicitly that consent procurement "rests 
upon each individual who initiates, directs, or engages in the 
experiment. It is a personal duty and responsibility which may not 
be delegated with impunity." The literal meaning of that last 
phrase, "with impunity," is "with freedom from punishment or pen¬ 
alty." It is my experience, by and large, that consent-getting is 
nevertheless regularly delegated to either nurses or house officers. 
This practice presents the kind of ethical issue, which in my judg¬ 
ment, is our foremost concern—a mode of behavior that contradicts 
the stated ethical principle. 

The consent process is complex enough in itself without this 
kind of obviously faulty procedure that could be easily remedied. 
Since Nuremberg, it has been generally acknowledged that a valid 


11 




consent rests upon and consists of three elements: information/ 
freedom, and competency. Thus, a consent is valid if it is 
secured from a patient or subject who is knowledgeable, who 
agrees voluntarily, and who is compos mentis (or who, in the case 
of legal or mental incompetency, is represented by a guardian). 

In this context, I would like to plead for abolition of the phrase, 
"informed consent," because it misrepresents (both intentionally 
and grammatically) what is required in a valid consent. 

But even if this misanthropic phrase should disappear from 
the medical lexicon, consents will remain problematic because it 
is difficult (perhaps, in an absolute sense, impossible) to assess 
precisely and accurately the extent to which any given patient or 
subject is informed, free, and competent in the consent situation. 

I have not found any consent situation (except, perhaps, for a 
genuinely elective procedure) which unambiguously satisfies pro 
forma the full range of interests signified by these elements. 
Moreover, I do not know of any single rule or protocol which in 
itself is comprehensive enough to guard all the contingencies and 
to guarantee adequacy. 

I do not, however, conclude that we should abandon the concept 
of valid consent or blunt our moral sensibilities sufficiently to 
enable us to accept a more imperfect model. Rather—and presuming 
the subject's competency, which among the three elements of valid 
consent is customarily the easiest to certify—I believe that it 
ought to remain the physician's personal and professional struggle 
to fulfill the criteria for valid consent, by heightened sensitivity 
to all the elements that comprise voluntary consent, and by strenuous 
efforts toward full and complete disclosure of information to the 
patient's understanding. 

Ideally, the consent situation is a covenant between persons, 
a fiduciary relationship, which is intended to guard and protect 
while simultaneously opening to larger possibility the common 
humanity of the parties to a shared goal. That way of viewing the 
consent situation is easily forgotten or neglected in the day-to- 
day routinization of research, or in the enthusiasm for a study. 

But acknowledgement of the consent situation as a fiduciary 
relationship, by both physicians and patients alike, will probably 
go farther than any formal requirement toward respecting both the 
spirit and the letter of the consent requirement. 

RISK-ASSESSMENT 

The Nuremberg Code asserts that "the degree of risk to be taken 
should never exceed that determined by the humanitarian importance 
of the problem to be solved by the experiment," and the Declaration 


12 






of Helsinki similarly expresses its formal interest in risk-assess¬ 
ment by stating in its "Basic Principles" that "clinical research 
cannot legitimately be carried out unless the importance of the 
objective is in proportion to the inherent risk to the subject." 

However/ none of the documents venture to define precisely 
what constitutes an ordinate or inordinate risk, although the 
Nuremberg statement does provide that "proper preparation should 
be made and adequate facilities provided to protect the experimen¬ 
tal subject against even remote possibilities of injury, disability, 
or death." This commentary is not insignificant. Unlike the FDA 
requirement, which states only that drugs must be "safe" and 
"effective," but does not further explain or define these catego¬ 
ries, the Nuremberg statement offers some clues about which conditions 
constitute inordinate risk. 

Diagnostic precision must be developed in the applicability of 
clinical studies, just as there is need for technical and scientific 
excellence in research design. Those human trials that have treated 
indiscriminately the application of an innovative therapy have 
tended to be the most disastrous. For example, the use of a special 
high protein diet in the treatment of liver disease seemed to have 
a sound theoretical basis and to be administratively innocuous, but 
in the absence of the demonstrated benefit of this regimen, a decade 
passed before it became apparent that many patients were dying in 
hepatic coma as a result of this diet. That kind of risk appears 
to be inherent in any experimental study, but my point in citing 
this instance is to show that the risk need not be made inordinate 
by accepting a study as a success before adequate evidence is in to 
prove its validity. 

Withal, three things seem clear: (1) the risk factor will vary 
from study to study, depending on the nature of the disease, the 
condition of the patient-subject, and on other factors that are 
relatively unique to the situation; (2) the physician's initial 
obligation— primum non nocere is his minimal duty toward subjects, 
and their protection "against even remote possibilities of injury, 
disability, or death" is an appropriate extension of that basic 
desideratum; and (3) a good research design will identify both 
potential and/or anticipated risks and make provisions for unpre¬ 
dictable and unexpected risks. 

While these aspects of the ethics of human experimentation 
deserve careful consideration in every study that involves human 
subjects, they impact with special emphasis on research in the 
clinical setting. Anyone with experience in both kinds of investi¬ 
gations, i.e., when combined with professional care and when con¬ 
ducted in a non-therapeutic setting, knows that the personal and 


13 



interpersonal dynamics of these two settings can be, and usually 
are, remarkably different. For example, there is a heightened vul¬ 
nerability among subjects who are also patients. This calls for 
uncommon sensitivity on the part of primary care physicians who are 
also, in these cases, clinical investigators. 

ETHICAL AND MORAL DILEMMAS IN THE RESEARCH SETTING 

There are ethical issues in clinical research that, like the 
poor, seem destined to be with us always. This is so largely be¬ 
cause it is the task of ethics to probe behind the "what" and the 
"why," and to reference action to an affirmative warrant by estab¬ 
lishing the truth and value claims of that warrant. So long as 
research behaviors probe and push against settled ethical bounda¬ 
ries, so long will it be incumbent upon us to reexamine and reassess 
our moral predicates. I know, of course, that remarkable and 
gigantic strides have been made in scientific and technical achieve¬ 
ment, and that most if not all of these achievements owe their 
genesis to research and experimentation. But I also know that the 
ethical dilemmas of society are not rooted there, and that the 
moral crises that confront us do not emerge from the risks that 
attend our scientific accomplishment or the perils that accompany 
the promise of our technological triumphs. 

Our ethical dilemma is actually a set of questions: Can we 
agree upon a common set of values? Is there a firm consensus 
among us as to what is true and good and beautiful? Can we 
assume that we share common notions of duties and rights? And 
our moral dilemma, correspondingly, interrogates our conduct; If 
we can agree upon the principles of virtue, can we then be clear 
and unconfused about the practice of virtue? I ventured to observe 
at the beginning that the ethical issues that confront us today are 
derived principally from incongruence or discontinuity between for¬ 
mally adopted professional affirmations and the embodiment of these 
ideals in the research setting. If that is so, our ethical predica¬ 
ment represents something of an inversion of the experimental hypo¬ 
thesis; in this instance our problem is not that "we need to know 
more in order to do better" but that "we don't do as well as we 
know." 


14 


REFERENCES 


1. Myrdal, G.: An American Dilemma. (2 vols.) Harper, New York, 
1944. 

2. Cf. 39 Federal Register No. 165 (23 August 1974), 40 Federal 
Register No. 154 (8 August 1975), et seq . 

3. The Nuremberg Code, ^n Trials of War Criminals before the 
Nuremberg Military Tribunals under Control Council Law No. 10. 
(Vol. 2) Washington, D.C.: U.S. Government Printing Office, 
1949, pp. 181-2. 

4. World Medical Association: Declaration of Helsinki: Recommen¬ 
dations guiding medical doctors in biomedical research involv¬ 
ing human subjects, ^n Ethics in Medicine: Historical Per¬ 
spectives and Contemporary Concerns (Reiser, S.J., Dyck, A.J., 
and Curran, W.J., eds.). Cambridge: The MIT Press, 1977, 

pp. 328-9. 

5. Cf. 39 Federal Register No. 165 (23 August 1974), 40 Federal 
Register No. 154 (8 August 1975), et seq . 

6. Ethical Guidelines for Clinical Investigation, adopted by the 
House of Delegates, American Medical Association, Proceedings 
of the House of Delegates, pp. 189-190, November 30, 1966. 


15 





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Discussion Summary 


Conference participants raised three principal questions fol¬ 
lowing the presentation of Dr. Smith's paper. 

First, who should an investigator consult (besides himself) 
to assess accurately the degree of risk and the scientific merit 
of a research proposal? It was suggested that there is no set 
formula to determine what the risks of a particular study might be 
to the research subject. 

In essence, it is the principal investigator who must assume 
responsibility for selecting the appropriate panel to assess a 
proposed study's risks. The principal investigator himself is 
certainly among those to assess the study's more scientific or 
technical risks, in addition to its scientific merit; but other 
experts also typically are invited to assess both the degree of 
risk and the importance of the study. 

The second question dealt with the subject's motivation to 
participate in a study. Historically, one of the most important 
thrusts in clinical research has been that the benefit of research 
accrues to the subject. Today, the research subject is frequently 
less able to benefit directly from the research in which he is 
involved. Thus, whatever benefit the research subject gains is via 
his membership in society. Given these factors, what motivates an 
individual to become a research subject? 

In large-scale studies, the question of personal benefit usu¬ 
ally is not raised between the research subject and the investiga¬ 
tor. Rather, the questions that are typically discussed deal with 
the issue of personal safety and whether certain people ought to 
be allowed to participate in certain studies. Thus, the consent 
mechanism looms large. 


17 


For example, on the one hand, consent forms should protect 
subjects from poorly designed, unsafe experiments. And on the other 
hand, consent forms should ensure that the subject is well aware 
of his or her involvement in the study. Thus, from one subject's 
perspective, the emphasis tends to be on protecting the study sub¬ 
ject, rather than on assessing the personal benefits to be gained 
from participating in a research study. 

A final question focused on the dividing line between social 
utility as a justification for clinical research, and the subject's 
rights to protection and safety. Discussants agreed that there is 
no formal prescription with which to determine where this imaginary 
dividing line lies. It was noted, though, that some countries em¬ 
phasize the social benefit to be gained from research using human 
subjects over the individual's rights. 


18 


Legal Aspects of Using Human Subjects 
in Environmental Research 

Michael V. Mclntire, J.D. 

Santa Monica, California 


In this presentation, I will discuss the principles of law 
that govern liability of one person to another when something goes 
wrong, as those principles might apply to persons using human sub¬ 
jects for environmental research. At the outset, I must tell you 
that there is no series of legal rules, no "do's and don'ts" for 
you to take note of and follow so that you can live happily and 
judgment-free ever after. The legislatures of the state and fed¬ 
eral governments have not addressed themselves to your legal prob¬ 
lems concerned with using human subjects in environmental research, 
nor have the appellate courts, as far as I know. Your problems, 
to use a hackneyed phrase, aren't exactly a household word. They 
are not problems that have excited the press or the public. The 
result of this absence of pre-established legal rules and guidelines 
means that you are on a frontier of the law. Like the pioneers who 
pushed westward beyond the reach of the settled communities with 
settled laws, your scientific endeavors have likewise moved you in¬ 
to an area where the law has not yet reached. So, I have this 
warning for those who came with pencils poised to record a series 
of rules which, if followed, will enable you to pursue your research 
free of significant legal concerns: You are about to be disappointed 
Instead, my message to you is this: As regards the legal implica¬ 
tions of your activities, you are going to have to adjust to the 
fact that you will be living with a great deal of uncertainty for 
many years to come. 


19 


When I say the law is uncertain, I don't mean it is nonexis¬ 
tent. It is not as though you are out in trackless, weightless 
space, starting from scratch. The past, it is said, is the pro¬ 
logue to the future. The frontier communities were guided by 
the laws and the rules of the communities they left behind when they 
drew up the new laws and rules that would shape their future. So, 
we too can get some understanding of the legal problems that lie 
before you by examining the development of the law in areas that 
are related to your own legal concerns. What I propose to do is 
review some developments of the law in areas that the courts and 
legislatures would be likely to look to for guidance. In doing 
so, I hope I can help you to understand how and why you, as 
scientists, may become involved with the law and with lawyers. 

A RESEARCH SUBJECT IS INJURED—^WHO'S RESPONSIBLE? 

Let's assume a hypothetical situation as the framework from 
which to discuss your legal rights and responsibilities in the 
event that a human subject of your research suffers injuries dur¬ 
ing the course of, or as a result of your experimentation. A man 
in his late thirties volunteers to be a subject in your research 
program. The man is interviewed carefully by your staff. He is 
told that he will be exposed to sulfur oxide gases in the air he 
breathes, and that he will be asked to perform certain physical 
activities, during which certain bodily functions will be electri¬ 
cally monitored. The volunteer is told that the combination of 
sulfur oxides that he will be exposed to is 10 percent higher than 
the amount normally present in the ambient air in a highly pollut¬ 
ed urban area, say, Gary, Indiana. 

The volunteer is told that the effect of this amount of gas 
in the air on humans has not been studied, and, as a result, the 
effect on the volunteer cannot be predicted. The volunteer is 
told that he is taking a risk for the benefit of scientific 
research. He indicates that he understands, and is willing to do 
so. The volunteer agrees to accept $4.50 per hour for a 48-hour 
period, during which he will be exposed continuously to control¬ 
led amounts of sulfur oxides. When the experiment has been under 
way for about 36 hours, the volunteer becomes violently ill and 
collapses. 

We've said that there is little law to tell us who is respon¬ 
sible for what in this precise situation. But what lessons are 
taught by our historical review of the law in related fields? 

The first lesson is one that you don't have to be a lawyer to 
understand and that is, the law is a great Monday morning quarter¬ 
back. The absence of definitive legal guidelines does not prevent 
the law from second-guessing your judgments. In fact, hindsight 


20 


is one of the mainstays upon which the law is based. So, lesson 
number one is: "The absence of an existing legal standard does not 
prevent you from being judged against a standard that has developed 
after the fact." A second general lesson is that, even if there 
were some court decisions relating to your case, they would not 
remove the uncertainty as to the legal consequences arising from 
a specific situation. Generalization is difficult because the 
rights and responsibilities depend so much on the peculiar facts 
of each case. Furthermore, different courts may decide the same 
issue in opposite ways. 

For example, in 1950, the New York Court of Appeals (which 
is what New York calls its Supreme Court) held that the manufactur¬ 
er of an onion-topping machine was not liable to a worker whose 
fingers were cut off when his hands caught on the machine's revolv¬ 
ing steel rollers. Although the injury could have been prevented 
by an inexpensive guard or a shut-off device within the operator's 
reach, the Court ruled for the manufacturer and against the worker, 
because the hazard was obvious. The Court said that the manufactur¬ 
er had no duty to protect the worker from obvious hazards. How¬ 
ever, in 1966, an Illinois Appellate Court held that a manufactur¬ 
er was liable for injuries caused when the operator's hand and arm 
were drawn into the unguarded rollers of a corn-picking machine. 

The Court said that the design of the machine, without guards against 
obvious hazards, was "unreasonably dangerous." 

In 1970, the California Supreme Court held a manufacturer of 
an earth-moving machine liable for the death of a worker who was 
run down by the machine because the machine's engine box prevented 
the machine operator from seeing clearly, despite the fact that 
the "blind spot" was obvious to the machine owner. I suspect 
that if the New York Court were now to decide the onion-topping 
case, its decision would be in line with the decisions of the 
cases in California and Illinois. So, lesson number two is: "Court 
decisions won't necessarily remove the legal uncertainty that sur¬ 
rounds your actions." 

the legal basis for liability 

I want to discuss some of the specific problems created in 
our hypothetical situation, but before I do, I have another dis- 
^2.aimer. I am going to talk about substantive issues, not the 
procedural issues lawyers often raise to prevent the real issues 
from ever getting decided. For example, I am not going to discuss 
the statutes of limitations, which enable a court to avoid deciding 
the substantive issues because the lawsuit wasn t filed soon enough. 
Nor will I discuss sovereign immunity—the rule that prevents some 
governments from being sued without their consent. 


21 






Returning to our hypothetical example, let's assume that the 
equipment functioned perfectly, but the operator carelessly 
allowed too high a concentration of sulfur dioxide to build up, or 
that he failed to observe warning signals, or otherwise "goofed," 
and that the operator's negligence caused the volunteer's injury. 
Under those assumed facts, the operator's employer and the opera¬ 
tor are liable to the volunteer. Liability is based on the con¬ 
cept, as old as American jurisprudence, that a person is respon¬ 
sible for his mistakes that cause injury to others, if he knew, 
or should have known, that others might be injured. This is the 
so-called "fault concept" which, although under fire, is strongly 
entrenched in American law. 

Now, let's assume that the operator was alert and following 
instructions but because of inadequate instruction, he did not 
know that the readings on the monitors measuring the volunteer's 
vital signs had exceeded safe limits. Under the fault concept, 
the laboratory would probably be liable. The laboratory was 
negligent in failing to properly instruct the operator. So, 
under the fault concept, before the laboratory can be liable, the 
laboratory, or its employee, must have been negligent, and the 
negligence had to be a substantial contributing factor to the 
injury suffered. 

However, the fault concept is not the only basis for the 
laboratory's liability. Another basis for liability is the con¬ 
cept that is often called "strict liability" or "liability with¬ 
out fault." Let's assume that the volunteer was injured because 
a monitoring device which would have warned the operator to reduce 
the supply of sulfur oxide gases did not operate properly. Assume, 
for discussion, that there was no way that the laboratory could 
have known about the defect in the monitoring device. In this 
case, the laboratory is probably liable to the volunteer, even 
though the laboratory is totally without fault. The basis for 
liability is public policy. 

LIABILITY AS THE CONSUMER'S SAFEGUARD 

In the last two decades, the courts, with the acquiescence 
of state legislatures, have been attempting to protect individuals 
from physical injuries caused by the ever-increasing number of 
complex gadgets in our technological society. The rules of strict 
liability, or liability without fault, were developed to protect 
consumers from goods that have a defect that could cause injury. 

But these rules have been expanded rapidly into other situations. 
For example, in most states, it is now law that a person who sells 
a defective product that is unreasonably dangerous to the consumer 
is liable for physical harm caused to the ultimate user, even 


22 


though the seller exercises all possible care in the manufacture 
and sale of the product. I strongly suspect that these principles 
of law will be applied as well to determine the liability of an 
environmental research laboratory to its volunteer human subjects. 

The trend of the law has been to extend the rules of strict 
liability to allow recovery by persons who are not consumers or 
users of a product, and also to hold liable persons who are not the 
manufacturers or sellers of a product. The California Supreme 
Court allowed a person who was injured in a head-on collision with 
another car, to recover from the ^nufacturer of the other car 
whose defect caused the accident. Similarly, the Michigan Supreme 
Court allowed a bystander injured by an exploding shotgun shell to 
recover from the ammunition manufacturer. 

On the other end, the courts have been allowing recovery against 
persons who dispense commercial services, as well as against per¬ 
sons who sell or manufacture a product. An example is the designer 
and constructor of a plant, who was held liable for injuries caused 
by an explosion that resulted from an improper repair of a tube in 

7 

a heat exchanger manufactured by someone else. 

Whether the rules of strict liability apply to persons render¬ 
ing "professional" services is still an open question, as is illus¬ 
trated by three cases arising out of New Jersey in the three-year 
period between 1967 and 1969. In 1967, in a leading case, a New 
Jersey Appellate Court held that the strict liability doctrine did 
not apply to a dentist sued by a patient when a hypodermic needle 
broke off in the patient's jaw. The Court held that strict liabil¬ 
ity principles do not apply to persons rendering "professional" 
services.® A year later, in 1968, a federal court applying New 
Jersey law held that strict liability was not applicable to a company 
that designed, engineered, and supervised the initial operations 
of a chemical plant, when an employee died after inhaling lethal 
dust generated by the plant's operation. The Court characterized 
the company's acts as "professional services," and on that basis, 
held that strict liability did not extend to the company. 

Then, in 1969, the New Jersey Supreme Court held a beauty 
parlor strictly liable for services that caused burns to the scalp 
and hair of a patron of the shop. Distinguishing the case of the 
dentist decided just two years earlier, the Supreme Court said the 
dentist was rendering "professional" services, while the beauty 
shop was rendering "commercial" services. In my opinion, this 
purported distinction between "commercial" and "professional" ser¬ 
vices is an illusory one that is difficult to justify. I suspect 
that in this age of consumerism, the case will soon come along 
that will cause some court to inter that distinction in the legal 
gjf^veyard, along with other discredited legal fictions. 


23 


LIABILITY IN THE LABORATORY 


A strong argument can be made that the rules of strict liabil¬ 
ity should be extended to apply to an environmental testing lab¬ 
oratory. The reasons the courts give for imposing liability on a 
manufacturer or seller of a defective product apply equally as 
well to the operator of a laboratory conducting tests using human 
subjects. Let's look at the reasons for imposing liability with¬ 
out fault, and then apply them to the environmental research lab¬ 
oratory. 

In a pioneer product liability case, the California Supreme 
Court held that a manufacturer of a power lathe was liable for 
injuries caused to the user of the machine because the machine's 
defectively designed set screws worked loose while the machine 
was operating. The Court said, "The purpose of such liability is 
to insure that the costs of injuries resulting from defective prod¬ 
ucts are borne by the manufacturers that put such products on the 
market rather the injured persons who are powerless to protect 
themselves.^ 

Two years later, the Illinois Supreme Court held the manufac¬ 
turer of a truck's brake system liable for damages suffered by the 
occupants of a bus that collided with the truck when its brakes 
failed. The Court thought that imposition of liability without 
fault was justified by the following arguments: 

• Public interest in human life and health call for 
the utmost legal protection. 

• The manufacturer who solicits and invites the use 
of his product, by advertising and otherwise, 
should bear the loss caused by such use. 

• The loss caused by a defective product should 
be borne by those who created the risk and 
reaped the profit from it.^^ 

Other reasons advanced in support of the rule imposing liability 
without fault on the manufacturer or seller of a defective product 
are: 

• Liability is an incentive to make safer products. 

• The manufacturer and seller are in a better position 
to discover the defect than is the consumer. 

• The manufacturer and seller can insure against the 


24 


risk, and recover the cost of insurance through 
the price structure. 

On examination, all of these reasons apply as well to the 
environmental research laboratory that injures its human subject, 
as they do to the manufacturer of a product that injures a user. 

The human subject is generally powerless to prevent an injury sus¬ 
tained in a laboratory. The laboratory solicited the subject and 
invited him to engage in the activity that caused the injury. The 
laboratory, not the volunteer, profits from the activity that 
caused the injury. The laboratory, not the volunteer, profits 
from the activity. The laboratory is in a superior position to 
discover the defects in the system and to insure against them. 

And the rule imposing liability on the laboratory will promote 
safety-consciousness and safer experiments. 

Thus, a strong argument can be made that the liability rules 
that govern manufacturers and sellers of products in the market¬ 
place should apply to research laboratories whose research involves 
human subjects. That being so, it seems appropriate to explain 
what is meant by strict liability, or liability without fault. 

THE OBVIOUS HAZARD: WHO'S TAKING THE RISK? 

Liability without fault does not mean that liability arises 
every time an injury occurs. For liability to arise, the injury 
must have been caused by a "defect" and the concept of "defect" is 
a complex legal issue. In general, a product is said to be defec¬ 
tive if it fails to meet the reasonable expectations of the consumer. 
Thus, the law does not impose liability when a consumer is injured 
by ordinary risks that can be expected. For example, a restaurant 
was not liable to a native New Englander for injuries caused by a 
small fish bone in a bowl of chowder.^* Similarly, a shoe manu¬ 
facturer was not liable to a customer who, while wearing the manu¬ 
facturer's shoe, slipped on a wet floor in a laundromat, because 
consumers know that shoes tend to become slippery when wet. 

However, the fact that a danger is obvious does not necessarily pre¬ 
vent the imposition of liability. A South Carolina court held a 
seller liable for injuries caused to a child whose hand came in 
contact with the unguarded blade of a power mower, even though 
the danger was obvious.^®The Illinois case that I mentioned ear¬ 
lier, involving the unguarded cornpicker, is another example of an 
obvious hazard still subject to liability. 

Thus, there is no clear rule for determining when liability 
may be imposed in situations where the harm was caused by an obvi¬ 
ous risk. The test seems to be whether the risk, or danger, was 
unreasonable, considering the seriousness of the harm, the chances 


25 



of its occurrence/ and the ease with which it could have been pre¬ 
vented. For example, a railroad may have no legal duty, and there¬ 
fore, no liability to install crossing gates on a little used coun¬ 
try road that crosses a single railroad track carrying three trains 
daily. The risk of an accident is slim because there are few cars 
and few trains. But the risk of an accident may be "unreasonable" 
if the road is a highway, heavily travelled by high-speed automobile 
traffic, and the gate could be installed relatively inexpensively. 

So, in our hypothetical example, the human subject knows that 
he is taking some risks. Therefore, the laboratory would probably 
not be liable for a temporary asthmatic condition, or for minor 
skin irritation, or for a sore throat caused by the experiments. 
These risks seem to be the kinds of risks a subject should expect. 
However, if the injury was permanent, i.e., lung damage, heart 
damage, or even death, the laboratory may well be liable because 
the risk of permanent health damage would probably be judged to be 
an "unreasonable risk." 

HOW MUCH RISK DOES THE SUBJECT ASSUME? 

Related to this problem of strict liability is the issue of 
"assumption of risk," which is often raised as a defense to liabil¬ 
ity. The rule is that a person who voluntarily and unreasonably 
proceeds to encounter a known danger cannot hold another liable for 
the injuries he suffered as a result of his actions. "Assumption 
of risk" means that the injured party knew of the defect creating 
the danger, and appreciated the significance of the danger to which 
he was exposed. 

Consider, for example, the case of the appliance repairman who 
sued the manufacturer of a pressure bottle that exploded, injuring 
the repairman. Despite the warning imprinted on the bottle, which 
read, "Do not refill," the repairman refilled the bottle, which 
originally contained Freon gas, with oxygen, and used it to blow 
dust off of appliances he was working on. In the process, the 
bottle exploded. The bottle manufacturer settled the case by mak¬ 
ing a substantial payment to the repairman. Because the warning 
was sufficiently ambiguous as to the possible dangers of refilling 
the bottle, it was difficult to prove that the repairman assumed 
the risk. The warning could have been interpreted as an effort to 
prevent possible impurities from entering or forming in gas used 
in the refilled container. 

In the hypothetical example, the voluntary nature of the sub¬ 
ject's actions (i.e., the absence of pressure or coercion) may be 
shown by the low amount paid to the volunteer. A sum of $4.50 an 
hour is not enough to coerce anybody to participate in a research 


26 


experiment* But the same low payment also supports the volunteer's 
argument that he did not intend to subject himself to the kind of 
serious risks that injured him* Who among us would voluntarily risk 
permanent health damage for $4*50 an hour? 

Assumption of risk in products liability cases is tough to 
prove* I think that in the research situation, assumption of risk 
will be almost impossible to prove* A laboratory that injures a 
human subject while doing research on that subject to learn the 
extent of the danger of a substance will have some difficulty con¬ 
vincing a jury that the subject knew, understood, and voluntarily 
accepted that danger* 

There is one other aspect of the law that should interest you* 
If the defect that caused the harm was a defect in machinery that 
the laboratory purchased elsewhere, then the laboratory can proba¬ 
bly, recoup the money it must pay the injured volunteer from the 
manufacturer and the seller of the defective equipment* 

In summary, then, a laboratory is liable for the injuries suf¬ 
fered by a human research subject if the injury is caused by the 
negligence of a laboratory's employees* Furthermore, the labora¬ 
tory is probably liable, even in the absence of negligence, if the 
injury was caused by a defect in the laboratory system, or in its 
operation* How can you avoid this liability? The answer is, you 
can't* You must learn to live with it* In the long run, the best 
defense is to keep the safety of your human subject uppermost in 
your concern* Fully disclose the risks as you see them, do your 
best, and buy a good insurance policy* 


27 


REFERENCES 


1. Campo vs» Scofield (1950) 301 N»Y» 468, 95 N.E* 2nd, 802. 

2. Wright vs. Massey-Harris, Inc« (1966) 68, Illinois Appeals 
2nd 70, 215 N.E. 2nd, 465. 

3. Pike vs. Frank G. Hough Company (1970) 2 Cal. 3rd 465, 467 
Pacific 2nd 229. 

4. Restatement 2d, Torts, Sec. 402A. 

5. Elmore vs. American Motors Corp. (1969) 70 Cal. 2d 578, 451 
P2 84. 

6. Piercefield vs. Remington Arms Corp. (1965) 375 Mich. 85, 133 
N.W. 2d 129. 

7. Texas Metal Fabricating Co. vs. Northern Gas Products Corp. 

(Kan., 10th Cir. 1968) 404 Fed 2921. 

8. Magrine vs. Krasnica (1967) 94 N.J. Super. 228, 227 A.2d 539, 
aff'd sub nom Magrine vs. Spector (1968) 100 N.J. Super 223, 
241 A2d 637. 

9. La Rossa vs. Scientific Design Co. (3d Cir 1968) 402 F2 937. 

10. Newmark vs. Gimbels, Inc. (1969) 54 N.J. 585, 258 A2 697. 

11. Greenman vs. Yuba Power Products, Inc. (1962) 59 Cal 2nd. 57, 
377 P.2nd 897. 

12. Suvada vs. White Motor Company (1965) 32 Ill. 2nd, 612, 210 
N.E. 2nd 182. 

13. Webster vs. Blue Ship Tea Room (1964) 347 Mass. 421, 198 N.E. 
2d, 309. 

14. Fanning vs. Le May (1967) 38 Ill. 2d, 209, 230 N.E. 2d, 182. 

15. Sanders vs. Western Auto Supply Company (1971) 256 S.C. 490, 
183 S.E. 2d, 321. 


28 

















Discussion Summary 


Participants considered a situation in which neither the in¬ 
vestigator nor the subject was aware of the subject's hypersensi¬ 
tivity to a given substance, and subsequently, the subject collapsed 
in the middle of the experiment. Who would be held liable in this 
case? This question is one that has not yet really been answered. 
Some state supreme courts have held that if there was no way that 
the subject's hypersensitivity could have been predicted, the lab¬ 
oratory cannot be held liable. 

However, other courts, based on the information that one per¬ 
cent of the U.S. population is hypersensitive, held that the experi¬ 
menters should have issued some sort of warning to the subject prior 
to the experiment, and thus, they may be held liable. 

If the situation is such that the subject would not have been 
injured had he not participated in the experiment, the laboratory 
will probably be held liable. 

Participants questioned whether review board members have ever 
been held liable for quoting a subject's test data. In general, re¬ 
view boards are not held liable in this situation unless the review 
board itself is the entity conducting the experiment, as sometimes 
happens. 

Other discussion focused on the extent to which a funding agen¬ 
cy can be held liable for a subject's injury. Is a funding agen¬ 
cy, e.g., the EPA, responsible if a subject in one of its funded 
experiments is injured? A funding agency can be sued, but whether 
the case will be won depends on the extent to which the funding 
agency was involved in the experiment. A number of cases in other 
areas of liability have exonerated funding institutions from liabil¬ 
ity. For example, in the case where a bridge contracted by the 


29 


Federal Department of Transportation collapsed, the Department was 
not held liable because it had little to do with the construction 
of the bridge, aside from a review of its size and location. 

In a case where equipment furnished by the federal government 
to the grantee is the cause of injury, the government could easily 
be held liable, assuming the government agrees to be sued. In a 
case in New York, a sailor was injured by an aircraft carrier cata¬ 
pult constructed by a contractor to the U.S. Navy. When the sailor 
attempted to sue the federal government, the Department of Defense 
claimed sovereign immunity. 

Although the court backed the Department's decision not to 
be sued, it felt that the sailor should be able to recover damages 
from somebody. So, even though there was no proven defect in the 
catapult, the manufacturer was held liable because it was the only 
source with money enough to pay damages. This is called the "deep 
pocket" theory; that is, the court recovers damages from the party 
with money enough to pay for the damages. 

A final discussion was concerned with whether a laboratory 
can be held liable for long-term adverse effects suffered by re¬ 
search subjects. Whether a laboratory is found liable depends on 
the severity of the experiment's aftereffect, and whether the sub¬ 
ject was fully aware of all the risks to which he would be exposed. 
If the long-term effect is not serious, chances are that the labo¬ 
ratory will not be held liable because the subject knew he was ex¬ 
posing himself to some element of risk. However, if a subject suf¬ 
fers serious consequences as a result of an experiment, the labo¬ 
ratory may be held responsible. 

Nevertheless, the chances of a laboratory being held liable for 
the long-term effects a subject suffers diminishes with the passage 
of time because it is hard to trace fault back to an experiment 
that was conducted several years earlier. 


30 


Informed Consent—Its Function and 
Limitations 


Charles E. Daye, J.D. 
School of Law 
University of North Carolina 


Space limitations make it impossible to fully discuss all the 
potential ramifications of the issue of informed consent as it re¬ 
lates/ or might relate, to environmental research. In truth, I 
feel an even more distinct limitation in that I do not have a full 
or detailed understanding of the kinds of research being conducted. 
Accordingly, I had to make certain assumptions. 

ASSUMPTIONS AND CAUTIONARY NOTES 

General Assumptions 

I understand that certain tests or experiments, which have to 
do with the effects on human beings of certain kinds of environmental 
conditions, are conducted under clinical and controlled conditions. 
For example, I understand that individuals participating in your 
research might be exposed to various levels of carbon monoxide in 
order to determine certain human responses or responses of the human 
body to such exposure. I fully understand that this is only an 
example of the kind of research that is being conducted, but that 
it is, in a general way, reasonably representative of the kinds of 
research being done. 

In addition, I made certain assumptions about why the medical 
profession is concerned about the question of informed consent. 


31 



In general/ my assumption is that the informed consent question is 
important because of the ethical considerations that environmental 
research might raise. However, I make no pretense in that direction 
and I will leave these issues to those more qualified to speak on 
the subject of ethics. I do assume that this research is perform¬ 
ing a valuable service for society and that researchers are inter¬ 
ested in continuing research without incurring the societal dis¬ 
approval that might come about if individuals participated without 
having granted their informed consent. I further assume that doc¬ 
tors are interested in the basic legal principles regarding informed 
consent so that they may avoid, as nearly as possible, exposure to 
legal liability for money damages to research participants. Addi¬ 
tionally, I assume that to the extent that legal principles may be 
unclear so that one cannot advise absolutely how to avoid exposure 
to liability, that doctors nevertheless wish to have pointed up the 
best ways to avoid any potential liability. 

Even with these assumptions, I think it would be improper and 
unwise for me to offer "legal advice" in its true sense about any 
specific procedures or problems that have been or may be encountered 
in environmental research. First, I do not consider myself an 
"expert" on the subject of informed consent in the scientific re¬ 
search context. Second, as I have indicated, I have not evaluated 
any particular areas of research nor any methods employed to secure 
a participant's informed consent. My perspective, then, is that I 
have a professional acquaintance with the legal doctrine, if we can 
call it that, of informed consent in general. I emphasize that I 
do not propose specific solutions to any kinds of particular prob¬ 
lems, but will discuss general issues, problems, and principles as 
they may relate to environmental research. I emphasize, in partic¬ 
ular, that my remarks should not in any way be deemed an adequate 
substitute for a detailed analysis of the informed consent problems 
by legal counsel employed for that express purpose. 

Some Further Cautionary Notes 

The development of the informed consent doctrine did not arise 
in the particular context of general scientific research. The doc¬ 
trine arose in the context of the medical profession and involved, 
most particularly, the relationship between a doctor and his patient. 
The context out of which the doctrine developed has certain impli¬ 
cations for our analysis. 

First, since the doctrine arose in the context of the doctor- 
patient relationship, generally the problem concerned therapeutic 
procedures. For our purposes, therapeutic procedures may be defined 
as those procedures concerned with direct attempts to provide remedies 
for perceived ills of a doctor's patient. The doctor-patient 


32 



relationship has traditionally been one which we lawyers speak of 
as "fiduciary." That word is simply a fancy way of saying that a 
patient places a trust and a faith in his doctor. 

Second, the doctor-patient relationship, in a therapeutic con¬ 
text, may permit a doctor certain kinds of latitude that may not 
be available to a scientist/researcher conducting research in a 
nontherapeutic context. I refer specifically to a doctor's "thera¬ 
peutic privilege" which might permit the doctor to withhold certain 
kinds of information from the patient in certain kinds of situations. 
For example, a doctor is not required to disclose a risk to a pa¬ 
tient when disclosure of the risk to the patient would be contrain¬ 
dicated in light of the patient's medical condition. For the pur¬ 
poses of this paper, I have assumed that a scientist/researcher 
would not have such a privilege. 

The third consequence of the nontherapeutic situation relates 
to the fact that persons participating in nontherapeutic research 
do not have an expectation of a cure or other remedy to some per¬ 
ceived medical ill as an inducement to participate in research nor 
as a justification for his participation. Accordingly, I have 
assumed that in a nontherapeutic context, the inducement to a per¬ 
son to participate in research is some reason other than an expec¬ 
tation of a direct, personal, medical benefit. This may have cer¬ 
tain consequences when we speak in terms of factors that might in¬ 
duce one to participate in an experiment. This, in turn, may bear 
on issues such as voluntariness and free choice. 

Also, in the therapeutic situations there are various kinds of 
exceptions to a physician's or medical person's duty to fully dis¬ 
close relevant information, for example, in the treatment of mental¬ 
ly incompetent persons, insane persons, persons under the influence 
of drugs, persons subject to a "medical emergency," and the like. 
Additionally, legal issues may be raised if participants are chil¬ 
dren or minors. Since these are specialized issues I have omitted 
them from my discussion. 

To recapitulate, I have made the following assumptions: 

1. that environmental research is nontherapeutic research in 
which no benefit to a participant in the research in the form 
of a direct medical remedy is expected, 

2. that this environmental research is directed toward the 
pursuit of important societal objectives, but that these are 
benefits that would flow only indirectly to a research 
participant, and 


33 


3. that research subjects are in all respects legally 
competent to grant consent, i.e., persons of sound mind 
who are of sufficient age to personally grant consent. 

Finally, I must caution that the law of informed consent 
that I shall discuss is not uniform in all particulars. It is 
not uniform because it is being developed simultaneously in 50 
different states by state courts applying what we lawyers call 
the "common law," and in several instances, by state legislatures. 
Thus, to speak of "the law" of informed consent is inaccurate. 
Nevertheless, there are certain general principles to which we 
can refer with fair accuracy for our purposes. But complete 
accuracy would require analysis of the cases and laws of the 
states where the research is conducted. 

HISTORICAL PERSPECTIVES ON THE CONSENT ISSUE 

With these assumptions and cautions in view, let us now turn 
to certain historical perspectives on the consent question, since 
this may "inform" our consideration of its application in modern 
contexts, such as the scientific research context. 

No doubt, the foundation from which we derive our current doc¬ 
trine of informed consent can be traced rather directly to the law's 
very early recognition that "every human being of adult years and 
sound mind has a right to determine what shall be done with his own 
body." This statement, which is general in the law, recognizes the 
human being's right to self-determination and personal autonomy. 

Accordingly, it was very early in its development that the law 
recognized that any interference with personal integrity or with 
the "inviolability" of a person's body is a violation that the law 
is prepared to remedy by assessing damages. As a corollary of this 
right, there naturally had to be developed a doctrine stating that 
if a person consented to an invasion of his personal integrity, 
which otherwise would constitute a legal wrong, the very existence 
of that consent precluded the invasion from being wrongful. As 
illustrations, we can quickly see that a punch in the nose is an 
offense to one's bodily dignity if it occurs between strangers on 
a street corner. Conversely, we can quickly recognize that precisely 
that same punch in the nose when it takes place in a lawful boxing 
match does not expose the person doing the punching to liability. 

It was precisely the central concept of personal dignity and bodily 
integrity that gave rise to a doctrine in the law of torts that is 
known as "battery" (or sometimes inaccurately referred to as 
"assault"). The "black letter" definition of battery is "any inten¬ 
tional touching of another which is harmful, or offensive to a rea¬ 
sonable person." 


34 



The ingenuity of human beings to vary their conduct naturally 
required further development of this legal doctrine. For example, 
consider the case of a person who went to the hospital for a check¬ 
up, who was approached by a doctor, placed under anesthesia, and 
then operated on. For example, let us say that the person's appen¬ 
dix was removed. Now clearly this is distinguishable from a punch 
in the nose between strangers on a street corner. But is it never¬ 
theless an invasion of the person's bodily integrity if the person 
was not in the hospital for the purpose of having his appendix re¬ 
moved and had authorized no one to undertake such a procedure? The 
problem is that the doctor in question was not actuated by any evil 
intent or desire to do harm. That, however, was not essential. 

The courts had no trouble finding that the operation in those cir¬ 
cumstances was an invasion of the person's bodily dignity, because 
the "invasion" occurred without the consent of the person on whom 
the operation was performed. That person could sue the doctor in 
a torts action for battery. In other words, because the touching 
was not consented to and because in the absence of consent it was 
wrongful, it exposed the one who did the touching to liability. 

Similarly, we can imagine instances in which a man represented 
himself to a woman as "a doctor," secured her consent to a physical 
examination, and proceeded to perform that examination. The woman 
subsequently discovered that his statement that he was a doctor was 
true, but that in fact he was a Ph.D. and not an M.D. When this 
situation arose, the courts had little trouble in finding that, 
of course, consent to the touching had been granted, but that it 
had been granted pursuant to fraud or misrepresentation and was 
completely ineffective. Naturally, that would lead to the liability. 
It may be instructive to point out, based on the preceding hypothe- 
ticals, that it is immaterial whether the patient operated on in 
fact needed his appendix removed or whether the doctor who removed 
the appendix had done so with every degree of skill and care. 
Similarly, it is irrelevant whether the Ph.D. knew how to conduct a 
physical examination and did so with every possible skill. The 
nonconsensual removal of a bodily organ, even diseased, would vio¬ 
late the very principle that without consent the touching was un¬ 
authorized, and without any consent to the touching, it was unlawful. 
So too would the physical examination be considered wrongful where 
the consent had been obtained under false pretenses. 

Over the years, other situations developed. The classic case, 
perhaps, is that of a woman who went to the hospital and consented 
to an operation on her left ear. When placed under anesthesia for 
that purpose, the physician discovered that her right ear needed 
the operation more than her left, and proceeded to ignore the left 
ear and operate on the right ear. Without any allegation that the 
operation was not performed skillfully in every respect, the 


35 


plaintiff sued the doctor and contended that he had no consent to 
operate on her right ear. The court agreed. It held that the 
operation on the right ear was indeed an unlawful invasion of the 
plaintiff's body, and was a battery because it was done without 
the plaintiff's consent. The question naturally could not be 
avoided whether indeed the plaintiff had not consented to an opera¬ 
tion of the precise character as the one performed, except on another 
part of her body. It could be suggested that the plaintiff had 
given consent to an operation, which was true. The consent, how¬ 
ever, was limited to an operation on the left ear. Out of this we 
derived the legal principle that consent may be granted but that 
the consent must not be exceeded. 

Then cases arose in which, for example, a patient had consent¬ 
ed to an "exploratory operation," and that in the course of the 
operation the doctor removed a diseased organ. Having consented to 
the "exploratory operation," the issue naturally arose as to whether 
the plaintiff also had not consented to the removal of the diseased 
organ. The doctor thought "exploratory" meant "if you find a disease 
do what in your medical judgment seems indicated." The plaintiff 
thought "exploratory" had its common meaning of "look and see." 

Since patients are medically untrained, the courts came to the posi¬ 
tion that it was up to the doctor to make sure the patient under¬ 
stood what was meant if the terms used had meanings other than those 
that untrained lay persons ordinarily would accord to them. In many 
cases, except those in which life or serious consequences might be 
threatened by failure to remove the organ discovered to be diseased, 
the courts did not hesitate to find that the removal of the organ 
without the patient's consent did indeed violate the principle that 
every person had a right to determine his bodily integrity. Gener¬ 
ally speaking, the courts that looked at the problem in its early 
stages considered this matter to be a battery. 

Then a series of cases arose in which the patient consented to 
a medical procedure, and that procedure was carried out with skill 
and competence, but, for example, the incision did not heal, some 
other organ was damaged during the operation, or the patient con¬ 
tracted a disease as a result of the operation. The courts had 
some trouble with this problem in that the patient had consented 
to the precise procedure undertaken, but it had not produced the 
results that both the patient and the doctor reasonably expected. 
While each person reasonably expected positive results, by reason 
of medical training and skill, as well as experience, the doctor 
knew that in certain kinds of procedures risks exist, for example, 
certain complications occur with a more or less statistically pre¬ 
dictable frequency. The patient had not known of these risks. 

The earlier cases to rule on the problem found that the failure of 
the doctor to disclose potential risks of the procedure, of which 


36 




he was aware, vitiated the consent granted by the patient. Upon 
holding that the consent was not effective, it followed that a 
battery had occurred. 

Beginning around 1960, however, courts began to recognize 
that the problem did not really involve an invasion of the bodily 
integrity without consent. Nevertheless, they were mindful of the 

notion that originally gave rise to tort of battery-that an 

individual ought to be able to exercise self-determination with 
respect to his own body. Accordingly, the view began to be devel¬ 
oped that the real problem was not the absence of consent but that 
that consent had been granted upon inadequate or insufficient in¬ 
formation about the risks or potential complications of the treat¬ 
ment. The courts found implicitly in these situations that the 
patients had relied on their doctors for information and the doctors 
had failed to provide enough information. In this light, the prob¬ 
lem did not look like battery, which we saw earlier as a punch in 
the nose between strangers on a street corner, but more like a prob¬ 
lem arising out of the nature of the relationship between the doctor 
and the patient. 

When the doctor failed in that relationship, in areas not 
involving an absence of consent, the failure was treated as "mal¬ 
practice." Malpractice was in another branch of the tort law called 
"negligence." This treatment of the problem had certain legal con¬ 
sequences which I will omit since they are not directly germane to 
our discussion. Suffice it to say that the courts began to impose 
on doctors a duty, premised on their relationship to the patients, 
to inform patients of all the material information that would be 
necessary to enable patients to make an informed judgment as to 
whether or not to undergo a medical procedure. While not every 
court would articulate the analysis this way, in general, we may say 
that courts understood that the physician was an expert and the 
patient was not, that patients continued to have an exclusive right 
to exercise control over their own bodies, that consent premised 
on inadequate information was not fully informed, and that the 
patient was in complete dependence upon, and must trust in, the 
physician to provide information necessary to an intelligent and 
informed decision. 

Based on these considerations, one of the leading cases on 
the subject decided that the law should impose a requirement upon a 
physician to present to his patient all information relevant to a 
meaningful decisional process. Of course, the physician, by reason 
of his training and experience, could make an evaluation satisfactory 
to himself or herself. But the court's judgment was that the deci¬ 
sion was not the physician's to make. It was the patient s! 


37 




It was in this context that the failure to disclose relevant 
information was treated as a malpractice problem, that is, a 
breach of a physician's duty to his patient. 

DEVELOPMENT OF THE INFORMED CONSENT ISSUES 

General Statement of the Doctrine 


A general statement of the doctrine that has come to be known 
as "informed consent" may be attempted. The informed consent doc¬ 
trine provides that a doctor must provide a patient with sufficient 
information to enable that patient to make an informed and intelli¬ 
gent choice as to whether to undergo a particular medical procedure. 
When necessary to an informed and intelligent choice the information 
provided, generally speaking, must include the nature and magnitude 
of the direct risks attendant to the procedure, the methods and 
likely results of the procedure, the alternatives, if any, to the 
procedure contemplated, and the nature and magnitude of any collat¬ 
eral risks associated with the procedure. Failure to provide such 
information will make the doctor subject to liability if a risk 
which was not disclosed, but which could have been disclosed, results 
in harm to the patient, if the risk were such that if disclosed the 
patient would not have consented to the procedure. 

Elements of the Doctrine 


Having once made a general statement such as that above, it 
nevertheless becomes necessary to identify the precise parts or 
elements involved in the general statement and then we must attempt 
to apply those elements in the context of scientific research. 

Upon analysis, we will notice that the doctrine requires (1) 
that certain information be provided, (2) that the person granting 
the consent have an ability to understand and appreciate the nature 
of the information provided, and (3) that a willingness to undergo 
the procedure be voluntarily expressed. Accordingly, we may speak 
of the elements as "information providing," "use of information," 
and "voluntariness" of consent. 

With respect to information providing, in the context of medi¬ 
cal research, it would appear clear that information regarding the 
procedure and methods of the research must be provided. But that is 
not all. The doctrine of informed consent relates particularly to 
the providing of information about the known risks to which one may 
be exposed upon participating in the research. Any known risk of 
death or serious bodily harm must be provided, probably in every 
instance. 


38 




However, it appears that more information needs to be provided. 
Probably every potential adverse consequence of significance ought 
to be disclosed. However, in the context of environmental research, 
it is precisely the purpose of the research to identify risks that 
may be involved in a particular kind of environmental exposure. 

Thus, it seems that a clear and positive statement should be made 
of the extent to which risks of the research are unknown , together 
with a statement of the researcher's best judgment as to the nature 
of such unknown risks, as well as the magnitude of the possibility 
of any of the unknown risks coming to fruition. It clearly seems 
possible that scientific research may be involved with risks that 
are unknown and that, in the exercise of ordinary care on the part 
of the researcher, cannot be known. Thus it seems very likely 
that a failure to inform any participant in such research that there 
may be risks that are unknown would constitute a failure to provide 
adequate information. 

The second element dealing with the subject's ability to use 
the information provided relates simply to making the information 
available in a form that is understandable and comprehensible to 
the subject participating in the research. For example, if the 
subjects are lay persons, the use of scientific terms that might 
not be understandable ought to be avoided, or if not avoided, 
scientific terms ought to be defined in lay language. For example, 
there is a case involving a doctor who informed his patient that 
he wanted to do certain kinds of exploratory surgery for cancer of 
the breast. At the hospital the patient was given a standard form 
which indicated the procedure to be a mastectomy. The patient, 
remembering the doctor's description of exploratory surgery and not 
understanding the definition of mastectomy, signed the form. Dur¬ 
ing the operation the doctor discovered that indeed the breast was 
cancerous and removed it. The court held that the doctor could not 
rely on the patient's signing of the standard form of consent, not¬ 
withstanding its use of the term mastectomy, because the patient 
had no understanding of that particular term. It went on to hold, 
therefore, that her consent was not an informed consent. 

This is instructive in two respects. First, as indicated, the 
information must be provided in a form that is usable in light of 
the researcher's knowledge of the subject's education, training, 
language limitations, and similar factors. Second, the mere signing 
of a form will not necessarily protect the doctor, although the form 
itself in all respects may be adequate. This may be because the 
subject does not understand the terms in the form, or perhaps, 
because the subject did not properly or attentively study the form. 
In such a case, a serious question will be raised as to whether 
the consent granted was informed, notwithstanding that the subject 
signed a standard form of consent. 


39 





At this point I would emphasize that a form is a limited device. 
Generally speaking, a form is nothing more than a memorial of the 
meeting of the minds of the researcher and the subject. It is no 
substitute for the direct, personal provision of information. This 
does not mean that signed forms are not important. They are. They 
may be evidence of the information provided as well as the consent 
granted. They should not, however, in all cases, be treated as a 
substitute for a more effective method of providing information. 

The third element of the doctrine of informed consent relates 
to voluntariness. Voluntariness connotes, of course, a free-willed 
determination, on the part of the subject, to participate in the 
research. Naturally, coerced consent would not be effective. Coer¬ 
cion, of course, would exist in the case of a person who simply 
overpowered a person's free-willed exercise of determination by 
threats or force. But coercion may come about in many, many other 
ways. However, the greatest concern ordinarily in a research con¬ 
text would not be about direct coercion, but about, what I shall 
call, "coercion in the circumstances." This relates to who the par¬ 
ticipant is and the circumstances that surround a granting of consent. 

Some studies have investigated why people agree to be research 
subjects. In the case of doctor-patient relationships, in a thera¬ 
peutic context, participation may come about because of the trust 
and confidence the patient has in the doctor. I have assumed no 
such motivation would exist on the part of the participants in envi¬ 
ronmental research. I have assumed that these participants may be 
public spirited persons, needy persons, or persons who for some other 
reason are influenced to become subjects. I imagine that the induce¬ 
ment to participate in environmental research is probably monetary. 
While I think significant problems of voluntariness are not likely, 
researchers might want to keep in mind the nature of any inducement 
they hold out in light of the circumstances of the persons who might 
choose to participate. It is not inconceivable, although I think 
the possibility is remote, that the voluntariness of a consent might 
be questioned if subjects are persons who are in such dire financial 
needs that the exercise of free will may be precluded by the very 
circumstance of their need. 

Application of the Doctrine in Research Situations 

As I interpret the informed consent doctrine in the context of 
environmental research my advice would be that researchers provide 
their subjects with "all the information a reasonable person would 
want and need to know in order to make an intelligent and understand¬ 
ing determination of whether to participate as a subject or not." 

Who is a "reasonable person"? While that inquiry seems simple. 


40 




its explication is somewhat more difficult. For the purposes of 
environmental research, I would think there is a soundness in the 
assumption that a "reasonable person" is a person of ordinary intel¬ 
ligence, who possesses all the data that ordinary persons in the 
community possess. If you are dealing with other kinds of persons, 
the problem would become more significant. The concept of the 
reasonable person has a direct relevance to the first element of 
the doctrine of informed consent dealing with information providing. 
It is probably sound to suggest that information need not be provid¬ 
ed about things that a person in the community who has a sound mind, 
ordinary intelligence, and the average capacity for understanding 
would already know. I am not sufficiently knowledgeable about 
environmental research to know the exact implications of that state¬ 
ment. I would stress, however, that researchers should provide any 
information that a person of ordinary intelligence and common under¬ 
standing in the community would be unaware of. I would generally 
include in this any risks of the research, the procedures, the meth¬ 
ods, and any other information about the research that would be use¬ 
ful to a subject in determining whether to participate in a research 
project. 

In connection with the precise content and detail of the infor¬ 
mation that needs to be provided, the courts have formulated a doc¬ 
trine that all "material" information should be disclosed. What is 
"material" information? In an oversimplified way, it is any infor¬ 
mation that the reasonable person would consider important and want 
to evaluate in making a determination whether to become a subject 
in your research. For example, I think a court would be likely to 
hold that the possibility of a risk arising, a risk as low as one 
percent, if that risk would expose a person to death or serious bod¬ 
ily injury, is a "material" risk that ought to be disclosed. When 
the risk is one that does not involve a risk of death or serious 
bodily injury, the question is somewhat less clear. However, any 
risk that is known and would be significant should be disclosed, 
even if the risk is one that threatens only short-term discomfort of 
even a nonserious nature. I have already indicated that the very 
fact that certain risks may be unknown is itself a risk that ought 
to be disclosed. 

I think most courts would apply the standard that a risk, to 
be material, has to be a risk that would be material to a reason- 

person. In thoroughness, however, I should mention that some 
courts might hold that it is not a risk that would be material to a 
reasonable person, but a risk that would be material to the person 
undergoing the participation in the experiment . There is, of course, 
a problem here in that after a risk has come to fruition and injured 
a participant, that participant has every incentive to say that if 
the risk had been known, he would not have participated in the 

research. 


41 






In the medically therapeutic treatment context, there is a 
division of authority as to whether the standards that govern what 
information should be disclosed is a standard to be determined by 
the court as a matter of law, or a standard that is determined by 
what the medical profession would regard as the professional stan¬ 
dard for disclosure. The way the problem practically arises is as 
follows: Let us assume that in a research procedure a certain risk 

was not disclosed. The plaintiff would claim that the risk was a 
material risk. The researcher would counter that it is not the 
practice in the research profession to disclose such a risk. The 
question then is whether the standards of the profession should 
control what disclosure should be made or whether the court, as an 
independent matter, will determine what information should be dis¬ 
closed. 

In my judgment, the sounder and safer alternative for a re¬ 
searcher is to disclose all information that would be material to 
a reasonable person. By disclosing all the information that the 
researcher reasonably can disclose, the researcher avoids the 
possibility of failing to disclose something even competent re¬ 
searchers would not generally disclose, but which later might be 
determined by a court to have been something that should have been 
disclosed. 


Ultimately, it appears that there are three resolutions to 
the problem of what should be disclosed. There may exist an ethi¬ 
cal ideal of disclosure, a practical limit of disclosure, and a 
legal limit of disclosure. Presumably, the ethical ideal would 
require disclosure of everything. It may be practically impossible 
to make an ideal disclosure for many reasons, one of which is pro¬ 
bably related to the researcher's time and capacity for making dis¬ 
closure. Whether the maximum that could practically be disclosed 
is the legal minimum that must be disclosed is undetermined. It 
would be my advice, however, that to avoid a failure to disclose 
the legal minimum , a researcher ought to strive to provide as much 
information as is practically possible in view of all the circum¬ 
stances of the situation. The ultimate legal determination 
undoubtedly will rest on what the researcher "reasonably could 
have done in the circumstances." 

I now turn to the question of when a failure to disclose will 
result in liability. We may now assume that in a particular case 
there has been a failure to disclose a risk that a reasonable per¬ 
son would regard as a material risk, and that it was possible for 
the researcher to disclose that risk. Speaking practically, not 
every failure to make a disclosure will result in liability. A 


42 







failure to disclose a risk will result in liability only if an 
injury is caused to a person by the risk that was not disclosed. 

The problem is that in advance the researcher cannot determine 
whether a particular risk will result in injury to the research 
subject. By failing to disclose a risk a researcher would be 
taking a gamble. 

One other situation in the research context that might arise 
involves the following situation: Assume a researcher makes a 
disclosure of all the risks that he knows about, discloses the 
fact that certain risks are unknown, and after the research is 
under way, gains additional information that the subject, as a 
reasonable person, would desire to know. Is there a duty to dis¬ 
close information discovered after the experiment is under way? 

I am not aware of a case that has addressed this question. How¬ 
ever, it would be wise, I think, for the researcher to regard him¬ 
self as under a duty to make a disclosure at any point during the 
process of the research if he learns of risks that were previously 
unknown or learns of risks that are greater than, or different 
from those disclosed. 

One final matter that I think should be touched on deals with 
the question of whether a person must be informed at the outset, 
as part of the researcher's duty to make a full disclosure, that 
he may at any time withdraw from the experiment or the research 
program. No definitive answer can probably be given based on 
previous cases. However, it is reasonable to assume that if a 
person has an initial right to participate or not to participate 
after full disclosure is made, it seems likely that the right of 
non-participation continues throughout the process of the research, 
and that a person may withdraw at any time and must be informed of 
the right to do so. 

Situations are imaginable, however, where the withdrawal of 
the subject will have serious consequences to the validity of the 
study being undertaken and may impose a serious burden on the re¬ 
searcher. My best judgment is that these are burdens and disad¬ 
vantages that researchers must be prepared to tolerate. 

SOME PRACTICAL DIMENSIONS 

Without intending to suggest that the case law would require 
the following things that I shall mention, I would raise these 
additional matters for consideration. 

Who should make disclosure in a particular research program? 

It would probably be wise to have a person designated as responsi¬ 
ble for providing information to participants. The practical reason 


43 





is that such a procedure will avoid the possibility that one per¬ 
son will think another has given the appropriate information and 
that other person will be thinking someone else has done it. The 
consequence, as you can see, will be that no one would have given 
the information. This situation has arisen in instances, for 
example, in which the doctor thought the hospital would provide 
certain information, and the hospital, in turn, relied on the 
doctor to provide the information. The consequence was that the 
patient was not informed. A breakdown in the procedure for pro¬ 
viding information will not justify a failure to provide it. 

When should disclosure be made? It is not clear when disclo¬ 
sure should be made except to say that it must be made before the 
research begins. However, the provision of the information after 
the subjects are all assembled and are ready to undergo the re¬ 
search experiment may constitute a coercive circumstance in itself. 
No period for reflection, consultation with others, or sober eval¬ 
uation of the information provided may be available when the onset 
of the research follows too quickly after the provision of the 
information. Accordingly, it would probably be sound practice to 
provide a reasonable interval between the time when the information 
is provided and the time when the person is asked whether consent 
is granted. Perhaps no fixed time limit can be stated. The over¬ 
all circumstances would obviously be relevant. As a general rule, 
it would probably be safe to say that it would be good practice 
to permit a person whose consent is sought a sufficient amount of 
time between the providing of information and the request for con¬ 
sent, to permit the person to digest and reflect on the information 
provided and to make a sober and detached judgment about partici¬ 
pating. 

What about institutional review procedures? While it is doubt¬ 
ful that the existence of in-house procedures would avoid liability 
in circumstances where failure to disclose information has occurred, 
practically speaking, it would appear that the existence of in-house 
review panels, peer review groups, or research evaluation teams 
would be helpful in two ways. Institutional review procedures 
would make it more likely that all the relevant areas in which 
information can be provided are known. Second, review procedures 
act as a check on the researcher's own interest in carrying out 
research that might cause the researcher to take shortcuts with 
respect to the provision of adequate information. It may well be 
that the researcher's interest in conducting the research puts the 
researcher in a situation where something of a conflict of 
interest exists with respect to providing full information, parti¬ 
cularly if there is reason to suspect that the provision of full 
information might well hinder the assembly of subjects to partici¬ 
pate in the research. 


44 



Accordingly, as a safeguard against the possibility of the 
researchers taking shortcuts, which may result in a failure to dis¬ 
close, it would be good practice to have such review procedures. 

It can be seen that the review procedures relate to the relation¬ 
ship between the researcher and the research institution. Arrange¬ 
ments between the institution in which the research is undertaken 
and the researcher cannot ordinarily be thought to affect the rela¬ 
tionship between the researcher and the participants. 

What is the relevance of federal, state, or other legislation? 
Compliance with statutory requirements may well have a direct bear¬ 
ing on the reasonableness of the researcher's conduct in disclosing 
or not disclosing certain kinds of information. It would be sound 
practice to scrupulously comply with any statutory requisites. It 
is possible that failure to comply with statutory requisites may 
give rise to an argviment that the compliance failure itself estab¬ 
lishes the unreasonableness of the researcher's actions. 

What about federal agency regulations? The same thing that can 
be said about compliance with statutory requirements can be said of 
compliance with various applicable regulations of agencies. In 
addition, it may well be valuable to follow requirements of agen¬ 
cies that are administering the various kinds of research, because 
it may be that such guidelines or regulations will have been drafted 
by those who are thoroughly conversant with the issues of informed 
consent, and that by following them, the researcher will render 
less likely any liability for failure to meet the case law require¬ 
ments regarding the informed consent. 


45 



BIBLIOGRAPHY 


1. Annas, G.J., et al.: Informed Consent To Human Experimentation: 
The Subject's Dilemma. Ballinger Pub. Co., Massachusetts, 1977. 

2. Bogomolny, R.L.: Human Experimentation. Southern Methodist 
Univ. Press, Texas, 1976. 

3. Fried, C.: Medical Experimentation: Personal Integrity and 
Social Policy. American Elsevior Pub. Co., New York, 1974. 

4. Gray, B.H.: Human Subjects in Medical Experimentation. John 
Wiley & Sons, New York 1975. 

5. Hershey, N., et al.: Human experimentation and the Law. Aspen 
Publishers, Maryland 1976. 

6. Katz, J.: Experimentation with Human Beings. Russell Sage 
Foundation, New York, 1972, pp. 521-674. 

7. Katz, J., et al.: Catastrophic Diseases: Who Decides What? 
Russell Sage Foundation, New York, 1975, pp. 79-115. 

8. Posser, W.: Torts. West Pub. Co., Minnesota, 1971, pp. 104- 
105; 165-166. (Fourth ed.) 

9. Shannon, T.A.: Bioethics. Paulist Press, New York, 1976, 
pp. 209-291. 

10. McCoid: The care required of medical practitioners. 

12 Vanderbilt Law Review 549, 1969. 

11. Plant: An analysis of "informed consent." 36 Fordam Law Review 
639, 1968. 

12. Riskin: Informed consent: Looking for the action. 1975 Univ. 
Illinois Law Forum 580. 

13. Waltz and Scheunmeman: Informed consent to therapy. 64 North¬ 
western Univ. Law Review 628, 1969. 

14. Mohr V. Williams , 95 Minn. 261, 104 N.W. 12 (1905). 

15. Tabor v. Scobee , 254 S.W.2d 474 (Kentucky 1952). 

16. Bang v. Charles T. Miller Hospital , 251 Minn. 427, 88 N.W.2d 186 
(1958). 


46 






17. 

Nathanson v. Kline, 186 Kan. 393, 

350 P.2d 1093 

(1960). 

00 

• 

Nishi V. Hartwell, 52 Haw. 188, 473 P.2d 116 (1970). 

19. 

Canterbury v. Spence, 464 F.2d 772 

(1972). 


20. 

ZeBarth v. Swedish Hospital Medical Center, 499 

P.2d 1 (Wash. 


1973) . 



21. 

Cobbs V. Grant, 8 Cal.3d 229, 502 

P.2d 1 (1972) 

• 

22. 

Wilkinson v. Vesey, 110 R.I. 606, 

295 A.2d 676 

(1972). 

23. 

Fogal V. Genessee Hospital, 344 N. 

Y. Supp.2d 552 (1973). 


47 









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Discussion Summary 


Participants discussed whether increasing a subject's pay as 
a project progresses would be construed as a way of pressuring a 
subject to stay with a study until its completion. Discussants 
said that this procedure generally would not be considered 
coercive. 


49 


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Role and Function of Committees on 
Protection of Human Subjects in Research 


Edward Bishop, M.D. 
School of Medicine 
University of North Carolina 


As chairman of the Committee on Protection of the Rights of 
Human Subjects, I can assure you that membership is associated 
with problems. Therefore, I would like to discuss the problems 
of such committees as ours. 

I would like to quote from a recent issue of the American Bar 
Foundation Research Journal , in which Benjamin Duval states quite 
clearly one of the problems that a committee has, in that, "...an 
institutional review board is in itself a legal institution." The 
act that called for the establishment of these institutional review 
boards stated that the Secretary of Health, Education and Welfare 
must require the establishment of an institutional review board 
for every entity that receives funding. Therefore, although review 
boards are instructed not to approve proposals that will invade 
any subject's legal rights, the interests protected under such 
regulations are significantly broader than the legal rights of the 
subject. Benjamin Duval makes an interesting comparison when he 
says that institutional review boards ccxnbine the elements of an 
administrative agency and a jury. They also act as a legal author¬ 
ity to carry out laws and also to make laws. 

With that introduction, I can describe our ccmmittee's problems 
and methods by giving a brief outline of the methods we use at the 
School of Medicine at the University of North Carolina. We began 
our committee about five and a half years ago. Before that time. 


51 




the functions involved in institutional review had been carried 
out by a committee that was in charge of the Clinical Research Unit. 
Because of an increasing workload/ there was an obvious need for a 
specific committee to act as an institutional review board. Compa¬ 
rable committees exist in five other schools within the University. 
So, our committee was formed to function specifically as a medical 
school committee. 

Our committee's purpose and principles are best described in 
our Document of Assurance to HEW and in some words from the Arti¬ 
cles of Implementation. We feel that our function, as specified 
in our Document of Assurance, is to "fully protect the rights and 
the welfare of all subjects who participate in research, in inves¬ 
tigations, in study, in development, in demonstrations, or in other 
projects." Obviously, this includes many direct involvements, such 
as the action of drugs, medical and surgical procedures, and so 
on. But our committee has extended its responsibilities further 
than this, for example, to include non-invasive observations and 
data collection. We are concerned that there not be undue invasion 
of the subject's rights to privacy, and that there is no undue risk 
to the subject, at least not physical risk. The same is true of 
moral lights. 

One of the first obligations we had was to inform the faculty 
that if they plan to do human research, they must have their work 
reviewed in advance. Oftentimes, the investigator is reminded of 
this obligation when his funding organization will not consider 
his application until it has been reviewed by a board. 

Our primary obligation is to look at human rights, and not at 
the scientific merit of a research proposal. This is impossible 
because usually we must consider both aspects. If someone submits 
a frivolous scientific experiment, we would not accept it if there 
was any type of risk to the subject. On the other hand, there are 
times that the scientific merit and the amount of medical informa¬ 
tion to be gained do warrant some risks, and the experiment thus 
would be acceptable. We must in all cases have a balance between the 
two considerations, although the question of scientific merit is 
not our specific concern. Finally, we feel that one of our serious 
obligations is to make sure there is no undue enticement to persuade 
a patient to continue an experiment against his wishes. 

One of the other principles that we work under is that we feel 
that this is a serious committee, and therefore, it should have the 
representation of the most experienced and the senior faculty. 
Presently, the people who are on the committee, with only a couple 
exceptions, are people in senior positions at the University. We 
use these people, not because their age necessarily implies wisdom 


52 


or good judgment, but because they are familiar with the University. 
They are also familiar with the investigators and have their re¬ 
spect, so that if we on the committee disagree or need to advise 
the investigator, this guidance will come from a body that speaks 
with a certain amount of authority. 

Other important members of our ccxnmittee are the representa¬ 
tives of the public. I think, probably, we should have a greater 
representation from the commxinity, because the people who work on 
a voluntary basis, the public representatives, do an exceedingly 
good job. In reviewing research proposals using human subjects, 
the public representatives approach this task with a completely 
different point of view than we do, and oftentimes, they make 
very important judgments or find problems that we with our bias of 
a medical education, with our bias of seeing patients and subjects 
all the time, would have missed. We are not legally required to 
include public representatives on the committee, but including 
representation from the public or from the ccxnmunity is very 
strongly recommended. 

We differ from other institutional review boards across the 
country. For example, our committee meets only on a few occasions 
a year, and we do most of our review by mail. We do most of our 
voting by ballot. One of the reasons why we operate this way is 
because of the volume of our work. In a three-year period, we 
reviewed 297 new proposals; we reviewed for re-review 398 contin¬ 
uing proposals, or 695 proposals during this period of time. This 
COTies down to four or five proposals a week, 19 to 20 a month. I 
could not keep people on the ccanmittee if we convened twice a week 
to discuss these proposals, as we would have to, or once a week. 

I could not ask the representatives of the community to meet with 
us that often. This is the first reason why we do most of our 
work by mail review and by balloting. 

I think there are some advantages to this work procedure. In 
general, a proposal comes to my office when it has been reviewed 
by the principal investigator's departmental chairman. It is then 
reviewed by my staff for completeness to see that all the forms are 
in. There is a consent form and there is a review of the proposal. 
At some time this proposal may be given administrative approval. 
This is a right that has been given to me by a local committee. 

An illustration of administrative approval would be a proposal that 
has been approved, but has not been funded. Thus, the proposal 
has not been active, and the investigator wants to continue the 
approval process. The committee allows me to give administrative 
approval in other similarly benign or uncomplicated situations, 
but they in turn review at the next meeting of the committee all 
of my administrative approvals and sanctions, and in some cases, 
they deny approval. 


53 


Once a proposal is reviewed for completeness, it is sent to a 
subcommittee, and all the information that is sent to me, all the 
documents that come in for the research proposal, go to a subcommit¬ 
tee that goes through this package in depth. Then they report back 
to us. If the subcommittee reports a unanimous vote of approval, 
there are no problems, and a simplified form is sent to the full 
committee, who in turn ballot back again. If, however, the sub¬ 
committee says there is some problem; for example, if they are con¬ 
cerned about the use of human subjects in the project, then an ad 
hoc committee of experts in the appropriate field is appointed to 
review the proposal with the principal investigator. 

Now, I, as an obstetrician, cannot be expert on cardiac prob¬ 
lems. Our surgeon is not an expert on pharmacology. Therefore, 
we use members outside of our committee, and at times, outside of 
this University, to serve on the ad hoc committee to review with 
the principal investigator the proposal and to try to decide about 
the sticky problems. The subsequent report in turn comes back to 
the full committee, who now ballot by mail. They have the right 
to either accept the proposal, to request modification, or to 
reject the proposal. 

It has been decided that no research activity will be rejected 
without a majority vote, and that no research activity will be 
accepted without a majority vote. Actually we usually work on a 
unanimous vote. If I see that 12 members on a committee have 
accepted a research proposal, but one person picks up a very 
important but overlooked infringement of the rights of a human 
subject, then we will turn that proposal down, because I think we 
must lean over backwards to protect the subjects, even though the 
vote may have been leaning the opposite way. 

One reason why I like the idea of the mail ballot is because 
instead of having to make up your mind in a committee meeting at 
five o'clock on Friday, you have the opportunity to make up your 
own mind when you want to sit down and review these proposals when 
you feel like it, when you can give the time to it, and when you 
reach an adequate decision. So, I do feel that the balloting 
method is defensible, and we probably get better reviews than we 
would by sitting in a committee as a group. We do sit in a commit¬ 
tee as a group at regularly stipulated intervals, for example, 
when there is any division of opinion about a proposal, or when we 
need to speak to the principal investigator. 

The final decision of the committee is final and it is not 
questioned by higher authorities within the University. I think 


54 


it is stipulated by certain regulations that if we turn down some 
research activity, there cannot be pressures from the Dean, the 
Chancellor, the Vice-Chancellor, or from anyone else to change 
our decision. 

PROPOSAL REVIEW 

Out of 297 research proposals, we rejected only three. I 
think this is to the credit of the faculty at the University. 

They now recognize, not just because of the threat of legal lia¬ 
bility, the importance of human life. They do not submit research 
proposals that infringe upon the rights of human subjects or endan¬ 
ger their health in any way. When we did request modification of 
31 proposals, we were primarily asking someone to take out a risky 
portion, or what we considered to be a risky portion of their 
research proposal, or we asked them to modify their consent form, 
or, in some cases, an application was incomplete. If we had not 
requested and given the principal investigator opportunity for 
modification, we would have rejected more proposals. 

One of the problems that the committee has is the amount of 
work. Another problem we have is overlapping with jurisdictional 
problems between one school of the University with another. What 
if a proposal is a combined research activity between the Dental 
School and the Medical School; between the School of Nursing and 
the Dental School; who has jurisdiction? That question has not 
been solved yet and it has been a sticky problem, but I think it 
is an administrative problem. 

One of the other problems is, and I am not going to quote 
this directly, that the HEW regulations regarding review committees 
state that no matter how distant the research work may be from the 
granting institution or from the institution receiving the grant, 
that institution is responsible for protecting the rights of these 
research subjects. This regulation became very important to me 
a couple of years ago when we were funded for some research activi¬ 
ties in Chapel Hill. Those monies were being spent in India, in 
Pakistan, in Iran, and in a nxamber of European and Asian countries. 
We were legally responsible to those subjects in Charez. It was 
up to us to make sure they understood the consent forms they were 
signing—an almost impossible thing to do with any guarantee of 

completeness. 

This is a problem that is not only concerned with research 
conducted out of the continental United States; it is also a prob 
lem in cases where someone is doing research where part of the 
research subjects are located in a distant city, or when they are 
at a distant hospital. Do they use what we think is a consent form. 


55 


or what they think is a consent form? So far we have insisted that 
our consent form be used since we are responsible for research sub¬ 
jects. It is a problem for other institutions, other schools in 
the University that want to use patients of the medical school 
hospital. A professor of anthropology would like to talk to cancer 
patients to examine some aspect of their psychological reaction to 
their disease—can he do this? Who reviews his proposal? How about 
those people who just want to use record room reviews? Is this, 
even though they do not identify the subject, appropriate to do? 

ETHICAL PROBLEMS AND POLICIES 

Another difficult problem that is unsolved is the use of excess 
tissues and fluids. Someone says, "Well, when you send a tube of 
blood to the laboratory, they are going to use just 1 ml. I would 
like to use the other four. I do not want to get consent from the 
patient. I just want to look at the blood. I do not have to know 
who the patient is. I am not going to give any feedback to the 
patient. The blood is going to be thrown away anyhow." At first 
the idea sounds like "why not?" But you find that soon, the same 
person says, "A little extra blood is all right, but why don't you 
get another tube when you collect it? It won't hurt to get more 
than the one tube." Then you see you are infringing on a human 
subject. You are not going to harm him very much, but two tubes 
become four, or a little more cerebrospinal fluid. If you are 
doing some biological or pharmacological or biochemical test and 
you find that one of your samples now has evidence of some serious 
disease, do you have the right or the obligation to go back and 
search out that patient to tell him that he has some serious disease? 
These are some of the ethical problems that we have had, and we do 
have. We have not completely answered them. Finally, one of our 
present problems is that we review all human research done by the 
faculty of the Medical School. How about the research that is done 
on the patients of the hospital associated with the Medical School, 
that is not done by faculty? Who reviews that human research? It 
looks like the committee is going to be asked to do this. 

Another problem is concerned with the civil legal liability 
of the members of the committee. We have looked into this matter 
and we have known no instance when members of the committee have 
been held liable. But we have within this University one school 
whose faculty has suggested not serving on a committee until they 
have some liability insurance protection. I do not know if their 
threat is going to continue. The Chancellor's office has responded 
by saying that they will look into getting insurance for all of us 
who serve on such committees. That process is going on now. 

A final problem is, what is research? We say that we review 


56 


research on human subjects, but where is the dividing line between 
clinical care and research? We change our methods of doing a medi¬ 
cal procedure—and I have to use an obstetrical example. If we 
decide that all breeches should be delivered by Caesarean section 
rather than vaginally, and we keep a record to see how it works 
out, is that considered research, or is that just observation of 
what we hope is improved clinical practice? This is a difficult 
decision. Do you have to go to that patient and say, "You have 
a choice between a vaginal delivery and a Caesarean section"? 
Obviously, she cannot make that choice. 

Another problem we have is, when does research become accepted 
practice? Again, for obvious reasons, I use examples in the repro¬ 
ductive field. One faculty member developed a clip for steriliza¬ 
tion—obviously this was research. He wanted to see how successful 
the clip was, how many pregnancies resulted when this clip was used, 
was it better or was it worse than other contraceptive methods. 

After a period of time, he looked at a thousand or so subjects and 
said, "Well, my next thousand subjects—will they be considered as 
research subjects or have I already done the research? I know 
there were three pregnancies in the thousand, and the clip is avail¬ 
able clinically now." He says, "I am still going to collect datci 
on the clip because I am not sure how it is going to work out. It 
has not been tested long enough yet, but it is commercially avail¬ 
able." When does research become accepted practice? What about 
informing patients who have unexpected results or abnormal findings? 
Is it the investigator's responsibility to tell that patient? 

ADVICE AND CONSENT 

Finally, our biggest problem is with consent forms. First, I 
dislike the term "consent form." I do not think there should be 
a form for giving informed consent. There cannot be a standard 
form for an institution. There cannot be a standard form between 
different research activities. I think each consent form should 
be written in a language that the patient understands. This is 
where we can use our community members on the committee. If they 
cannot understand the consent form, then I am sure the patient 
cannot. The patient should understand what is being done, the 
benefits, the risks, the discomforts; whether there could be an 
alternative procedure other than the research procedure. 

Then, we ask that it be included in the consent form that the 
3 \ 2 bject is free to withdraw from the experiment without penalty. 

We try to serve as the research subject's advocate by saying that 
in the consent the subject should be told that if he feels his 
rights are being threatened, he can contact the Committee on the 
Pi^otection of Rights of Human Subjects. The consent forms have to 


57 


comply with the laws of this state, which may not be the laws of 
another state. 

Yesterday I received two research proposals. One consent form 
had three lines. It said the investigators were going to withdraw 
blood, 5 ml, and the patient is supposed to sign. That is about 
all the form said. It was not written in the first person. I think 
if you are going to consent to something, the consent form has to 
be written in the first person. 

The other consent form, believe it or not, was fourteen pages 
long. I think this is equally bad as the three-line consent form. 

I am not sure how many subjects will wade through fourteen pages 
to give consent to some research activities. I am afraid the 
committee may be at fault for pushing investigators to make sure 
that all the essential elements are on the consent form—we have 
made them make it quite voluminous. 

Finally, we do not like to act as a threat to the investigator, 
but rather, we like to act as a protector of the research subject. 

We are also protecting the investigator, not necessarily from any 
legal liability, but we are protecting him by helping him realize 
the rights of human subjects. 

In spite of regulations made up by committees, I am sure that 
research is going to continue. I am sure that research will contin¬ 
ue with human subjects, no matter how much basic or animal work can 
be done. New procedures, new agents must be tried on human subjects 
at some time. I think the continuation of review mechanisms such 
as ours will remain, and must remain, in existence for as long as 
they remain reasonable and acceptable. Finally, the most important 
thing in all circumstances is that the subject must be informed 
adequately before he gives consent. 


58 



Discussion Summary 


Participants discussed the advantages and disadvantages of 
having obstreperous members on review committees. On the positive 
side, participants felt that those who are apt to be meticulous 
about every point discussed in a committee meeting may bring up an 
issue that has been overlooked. A disadvantage is that this type 
of committee member may tend to disagree simply for the sake of 
disagreeing. In this case, some committee chairmen have the 
prerogative of deeming a committee member's objection as 
"unacceptable." 

Participants also discussed the need to keep bureaucratic 
overload in committees to a minimiim. Discussants felt that staff 
review of research proposals is justified in that these reviews 
reduce the amount of time spent considering proposals that are 
obviously unacceptable or missing required forms. 


59 



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METHODOLOGIES AND PROTOCOLS IN 
ENVIRONMENTAL CLINICAL RESEARCH 


Moderator: Ralph Stacy, Ph.D. 



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Developing Methodologies—Environmental 
Studies 


Steven Horvath, Ph.D. 

Institute of Environmental Stress 
Santa Barbara, California 


I would like to discuss a number of problems associated with 
the development of methodology, primarily from the non-invasive 
standpoint of investigating man under conditions of stress, whether 
the stresses are combined or single stresses. I would like to 
emphasize that most of our new procedures have been designed to 
work in multiple environments and under multiple stresses. 

CHARACTERIZATION: A PRE-TEST PROCESS 

I would like to start off by reviewing some of the basic things 
you do before developing a methodology. The researcher must effec¬ 
tively characterize the subject so he knows just exactly what he is 
going to do, what he is going to work with, and v^at he is going 
to do for the research subject from the standpoint of assuring 
that he has adequate safety in all of the procedures that will be 
employed. 

Sensitive Subjects 

Researchers have to contend with the problem of sensitive sub¬ 
jects and how you determine whether sensitive subjects are going to 
be in your pool, and what you are going to do with those subjects 
after you have them in your pool, or, in some cases, whether the 
researcher should set out to select a group of sensitive subjects 


63 



among a so-called normal population—not to look at individuals 
with disease, but individuals who are essentially considered to 
be normal in physiological terms, in both their pulmonary and 
their cardiovascular systems. 

Actually, we have had a problem with sensitive research 
subjects, because in almost all of our studies we have found one 
or two subjects who were sensitive to the particular pollutant 
that we were studying. In retrospect, it appears that we could 
have determined the subjects' sensitivity by using a question¬ 
naire. If you are going to study sensitive subjects, you 
should have those subjects available to you as sensitive sub¬ 
jects, and not have to include them as part and parcel of the 
overall population. 

Work Capacity 

A number of techniques of carefully categorizing an indi¬ 
vidual have been developed over the years. One of these tech¬ 
niques has to do, especially in air pollution studies or in 
toxicological studies, with evaluating the potential capacity of 
the subject to perform work. It has become apparent that one of 
the major factors in the response of an individual to a pollutant 
is whether or not he is active or inactive. Many of the studies 
that have been done on environmental pollution have used resting 
subjects, and have consequently missed the value of or the 
importance of the role the pollutant will play in the response of 
the subject, because most subjects exposed in a natural envi¬ 
ronment do have to work. 

The first evaluation of any subject has to do with his 
potential work capacity, and there are several ways that this 
work capacity can be measured. The best way, since almost 
everybody can walk—and this applies to individuals of all ages, 
anywhere from six to eighty odd years of age—is to measure their 
maximal aerobic capacity by having them walk on a treadmill that 
changes its rate. The treadmill can maintain a constant speed or 
it can change its speed, as well. You can perform this test very 
simply by a relatively straightforward technique. A computer 
gives the test results out immediately, so that you know not 
only the subject's ventilation, but also his oxygen uptake, his 
CO^ production, his body temperature, his heart rate, and his 
electrocardiogram as it is measured. 

Another procedure that we use to measure potential work 
capacity is the bicycle ergometer. There is an important dif¬ 
ference between the measurements made on a bicycle ergometer and 
those that are made on a treadmill. The difference is in the 


64 




neighborhood of 10 percent in terms of maximum aerobic capacity. 

When an investigator studies an individual using either a bicycle 
or a treadmill, he must take this into account. Furthermore, the 
position of the individual on the bicycle, whether he is in the 
upright position, or whether he is in a supine position, makes a 
further difference in his aerobic capacity. 

The question that arises here is, how are we going to determine 
whether or not an individual should perform a fixed load of work, 
namely, something like, say, 300 K cals per hour, or whether he 
should do work on the basis of a percentage of his capacity? One 
of the major factors that influences man's ability to perform is 
his age. As he gets older, past about 18 or 19 years of age, he 
generally shows a relative decline in his capacity to perform 
work. Therefore, if you utilize only a fixed workload, this may 
represent a considerable variation of the subject's capacity to 
do work. Consequently, it is almost necessary to measure the 
maximum aerobic capacity of the individual, so that you can relate 
the individual's performance under any stress in terms of percentage 
of his maximum aerobic capacity. Maximum aerobic capacity is 
influenced not only by age, but by the sex of the individual. 

Besides characterizing an individual by the percent of his 
capacity to perform work, and in terms of absolute fixed load, an 
individual can also be studied in another way, namely, in terms of 
a fixed ventilation. Some of the studies that we have done have 
utilized this characterization. A test of fixed ventilation is 
easily automated and very easily conducted under careful conditions. 

Body Fat 

Further characterization of the individual is necessary, and 
one of the things that we have found extremely important is to 
have some measurements of the subject's body fat, so that we can 
determine the lean body mass or the effect of protoplasmic mass. 
There are two basic techniques that are commonly employed to 
measure body fat. One is to measure the skin folds at various 
places—this is not the best technique, although it is probably 
utilized much more than any other. A much better technique is 
where you measure the individual under water. This technique 
utilizes some of the advances in technology. Instead of measuring 
the individual with an autopsy scale, we use load cells or string 
gauges to make these measurements. Individuals vary in body fat 
to a great extent, and some of the effects on the individual 
by pollutants are determined by the amount of body fat. 

We also utilize another type of technique, which is to measure 
people under water while they are exposed to various pollutants. 


65 



This is a new way of looking at individuals, and it is a fairly 
well automated technique. 

Blood Constituents 


Another factor in characterizing individuals, especially in 
terms of the effects on the individual, is blood constituents. 

This is a characterization that has been ignored for a long time. 

There has been a great deal of difficulty in some of the measure¬ 
ments that have been reported; namely, blood samples have been 
taken at unspecified times, and the measurements have been uncon¬ 
trolled in terms of position of the subject. Nevertheless, blood 
constituents are an important factor in characterizing research 
subjects, in that this characterization takes advantage of the 
fact that we know there are changes in plasma volumes, and that 
these will result in marked changes in the concentration of materials 
in the plasma, as a consequence of the subject being in different 
positions. 

NON-INVASIVE METHODOLOGY 

I would like to discuss more methodology techniques, starting 
off with measures of indirect methods of measuring cardiac output. 
There are a number of methods available; some are practical, and 
some are impractical. In general, we want to get away from the 
invasive techniques, which we use so commonly, and go over to non- 
invasive techniques. 

Of the non-invasive techniques, there are three that are 
potentially usable. One is the gas technique: the carbon dioxide 
re-breathing procedure, the nitrous oxide procedure, and the 
acetylene procedure. These are three fairly decent procedures, 
but they have some limitations due to the fact that they cannot be 
repeated at too frequent intervals. 

Another approach to measuring cardiac output, which has a cer¬ 
tain amount of value, that we have been utilizing to a great extent 
is the use of the impedance device. This method is—like all of 
these methods—not really as good as it should be in characterizing 
the resting individual, but it is extraordinarily comparable to 
direct methods, that is, the dilution techniques, if you use it in 
the individual who is active to any degree whatsoever. Unfortunately, 
this technique, although it is completely automated, can only be 
employed in individuals performing a slight activity, and only on 
the bicycle. The advantage of this technique is that you can leave 
the measuring devices on the individual for long periods of time. 

Thus, this technique detects rather striking changes that occur 
in the individual during the night. So, this is a fairly effective 


66 



technique for measuring cardiac output over long periods of 
time, with the least amount of interference to the subject. 


We have also tried using the echocardiogram to measure cardiac 
output. The only difficulty with the echocardiogram at the present 
time is the need for good microprocessing elements, and more impor¬ 
tantly, the need to be able to apply the test to an exercising sub¬ 
ject. So far, we have not had too much success using the echocardio¬ 
gram on exercising subjects, but I anticipate that very shortly we 
will have a device that will be very effective in this regard. 

Another indirect method of measuring cardiac output is to look 
at another part of the cardiovascular system, and that is, to 
measure the peripheral blood flow, whether you do it in the forearm, 
the lower leg, or in the finger. This is a completely automated 
technique over which neither the investigator nor the subject has 
any control. It is all automated, and can be timed. Instead of 
having to look at the old-fashioned records to derive the slope, 
the slope is derived electronically, and then the only calculation 
that has to be made is dividing the slope by a volume, which is also 
displayed automatically on the unit. The data are also put on a 
graph at the same time. 

This automated technique is a very new development in terms of 
measuring peripheral blood flow. It eliminates almost all experi¬ 
menter bias, and it is a very rapid procedure. In fact, you can do 
something in the neighborhood of 40 to 50 blood flows in a period 
of several minutes without any real difficulty to the subject. 

Investigators are faced with several path problems when they 
put subjects in an environment of 48®C. Test results indicate that 
people of different racial origins and different ethnic origins have 
a different response to exposure to a hot environment. Any time 
one studies subjects, one must characterize the subject not only in 
terms of his physical and medical characteristics, but in terms of 
ethnic origin, at least to some extent. 

A newer development has involved an examination of nasal 
airway resistance. We are now working with a device to measure 
both nasal airway resistance and oral airway resistance. This is 
an important new development, since it provides for separation of 
two portions of the respiratory system which have not been looked 
at too carefully in the past, and that is the point of time when the 
individual shifts from breathing through his mouth to breathing 
through his nose, or when there is a combined effect of those two 
functions. Microprocessors handle the calculations and the 
evaluations, and determine the pattern of the experiment. 


67 


Another factor that I think is of some importance is the need 
to develop devices that telemeter the heart rate. We measured a 
cross-country coach, and every time he saw any of his runners come 
by, his heart rate went up to 160, yet he gave the appearance of 
having no reaction to the race. Similarly, we measured the heart 
rate of a volleyball coach. His team lost the first set, won the 
next four, and despite the fact that during the entire period of 
time he sat very quietly, and apparently was unconcerned about the 
entire event, his heart rates went as high as 160. I might point 
out that his maximal heart rate was 180, so in that he is in a maxi¬ 
mal aerobic capacity test, he is under considerable stress. These 
studies indicate that many of the studies that we have been doing on 
subjects where we look at them and obtain measurements of the heart 
rate or using the electrocardiogram only at the fixed intervals may 
be missing a great deal. 

A few devices have been developed to make it possible to look 
at individuals non-invasively, and at the same time, to describe 
very simply the way in which a subject can be categorized by utiliz¬ 
ing, again, non-invasive techniques. The more effectively you can 
analyze the subject's response and his condition, the more effectively 
you can determine what is happening to the individual. 

One of the main advantages of the new methodology is not simply 
that researchers are able to utilize computer devices or new develop¬ 
ments in electronics to help build better instrumentation and to 
help organize the exposure of the individual, that is, to determine 
what he is going to respond to and how he is going to respond to it. 
More importantly, the new methodology has provided us with a means 
by which we can take the other techniques that are not usually 
available to us, from the standpoint of our own expertise, but which 
are commonly used in other areas, and by proper handling and working 
with electronics people, and with people who are interested in physi¬ 
ological response, it is possible to develop new devices that will 
make it easier for us to successfully invade the individual without 
doing it by an invasive technique. 


68 


Discussion Summary 


Ps^i^ticipants discussed the merits of using microprocessors 
rather than minicomputers in research activities* Discussants said 
that the minicomputers are more likely to break down than the micro¬ 
processors/ but the microprocessors are more adept at carrying out 
different operations simultaneously* Some laboratories use mini¬ 
computers as a supplement to the microprocessors* 

Discussants observed that the use of microprocessors has enabled 
investigators to automate the measurement of various bodily functions* 
In one participant's laboratory, the data that is obtained is tape- 
recorded to the IBM systems where it is analyzed* Tape-recording 
of data is an easy process, and the eight-channel capability enables 
the investigator to collect a good quantity of data* 

It was noted that although the development of automated analyti¬ 
cal procedures can be a timely and expensive process, these disad¬ 
vantages are offset by the tremendous amount of time the investigator 
saves in the long run once the automated units are set up* 

Participants discussed the steps the accumulated data goes 
through to be put into an analytic form* The automated units have 
a data base for each research subject that includes every measurement 
made on the subject* Statistical analyses are made from this data* 

The computer can immediately produce data on the basic body functions* 
To obtain derived functions, the base material is put on a data base, 
and then the various derived functions of statistical analysis of the 
computer data are carried out on the computer from the data base* 
Discussants noted that it is important to develop a data base that 
can be manipulated to handle large volumes of data* 

In a discussion of the differences between the Bruce system and 
the Balke technique, participants said that the Balke technique is 
more suited to studying populations of different ages than the Bruce 
system* For example, the Bruce system cannot be used to study 


69 


children under six or seven years of age, or on adults in their 
seventies and eighties. 

The Bruce system is used in some laboratories, but not for 
normal populations because there is no way of characterizing subjects 
throughout their entire life span or in relation to their sex. 

Participants also talked about the various methods of measuring 
blood pressure. Measuring blood flow by using radioisotopes is a 
viable technique, but it is invasive. An alternative is to use 
strain gauges to measure peripheral blood flow. Discussants said 
that attempts to automate the measurement of blood pressure have been 
unsuccessful, and that the best measurement is to use a blood pressure 
cuff and two good ears. 


70 


Rationale for Experimental Design 


John H. Knelson, M.D. 

Health Effects Research Laboratory 
U.S. Environmental Protection Agency 


I would like to describe how we decide what clinical environ¬ 
mental research we are going to conduct within the constraints im¬ 
posed by ethics# the law# and logic. I think it is very impor¬ 
tant, in discussing the rationale of experimental design, to bear 
in mind a few definitions and a few relationships. 

CLINICAL ENVIRONMENTAL RESEARCH; A DEFINITION 

Over the years that I have been involved in this type of 
activity, I have developed a simplistic definition of clinical 
environmental research. I think, as we expand our purview and 
bring new tools to bear on the topic, and as we learn a little 
more about the problems of environmental medicine, my simplistic 
definition will merit some scrutiny, and perhaps, need to be 
overhauled and expanded. But very briefly, the definition I have 
used is that any time you manipulate a human being and his environ¬ 
ment, you are doing clinical and environmental research. Now, 
what does that mean? More germanely, what doesn't it mean? When 
we study vdiat is happening to a population under specific circum¬ 
stances, or when we simply avail ourselves of the opportunity to 
study a population, I do not consider that we are conducting 
clinical research. 

I think some might argue with that, so I will give an example 
of vdiat I am talking about, that is, what we have been doing in 
Chapel Hill all along, and what most of our colleagues have been 


71 


doing around the country. In clinical environmental research, the 
siibject and his environment are manipulated. The subject is 
placed in an artifically-controlled environmental laboratory. You 
manipulate that person by putting him on a bicycle ergometer, on a 
treadmill, or by having him breathe through a pneumotachometer or 
into a spirometer, or in some other way study some aspect of his 
physiology. You do not allow the subject to range normally through 
his environment. Then you manipulate in a positive, very carefully 
thought out and contrived way, the subject's environment. You 
manipulate the environment by making it clean to a standard con¬ 
dition, putting the subject in a Class 1,000 or a Class 100 clean 
room, and the investigator gets a baseline of information. 

The investigator may manipulate the environment by having the 
subject breathe an air pollutant, or by manipulating the temper¬ 
ature, relative humidity, light intensity, sound levels, iso¬ 
lation, or other characteristics of the environment. This is the 
simplistic definition of clinical environmental research. I 
think, though, as we familiarize ourselves with the rapidly, 
exponentially growing technology that is available to us, we will 
need to enlarge that definition. 

Going back to one of the historical antecedents of clinical 
environmental research, one of the projects of the Harvard Fatigue 
Lab was to study the adaptation of workers to their new environ¬ 
ment as they constructed what was then called Boulder Dam. That 
project was certainly a form of clinical environmental research. 
Clinical research was done on these workers as they adapted to the 
new environment, but their environment was not manipulated. The 
subjects were manipulated only to the extent that some measure¬ 
ments were made concerning their adaptation. 

As we face the newer, more challenging, and more far-reaching 
questions that society will put to us with respect to our environ¬ 
ment, we will need to adopt a broader definition of clinical 
environmental research. For the most part, though, my discussion 
of the rationale involved in design experiments in clinical environ¬ 
mental research is based on the simplistic definition, where you 
put a person in a controlled environmental laboratory, and mani¬ 
pulate his environment in a predetermined, well-thought-out way. 

RELEVANCE: A KEY TO EXPERIMENTAL DESIGN 

The theme of my discussion is relevance. We are designing 
experiments and studies that have a very specific relevance to a 
question posed by society. Frequently, in other kinds of clinical 
research, much activity is pursued in a somewhat descriptive way. 

By that I mean that we are not really focusing before we undertake 


72 


the research, or before we design a particular study on a very 
precise question. We are exploring the results of a particular 
intervention, be it surgical or medical, and we do not have all of 
the consequences of that intervention completely in mind. 

The objectives, then, put in this simplistic paradigm of 
clinical environmental research, are to focus on a specific question 
that society is posing, and then to establish the experimental 
framework within which to address that question. If we do not 
keep these objectives in mind, we will conduct much clinical 
environmental research that will not be relevant to the questions 
that are being asked. 

I think we do need to keep in mind the relationship between 
clinical research, human experimentation, and probably, the other 
couple of ways that we can get at the answers to the same ques¬ 
tions. Much of the information that precedes the clinical experi¬ 
mentation, and much of the information that is the basis for the 
rationale of the experimental design, comes from two other disci- 
plines--basic toxicology and epidemiology. 

Basic toxicology has to precede and continue to be an inte¬ 
gral part of the rationale for clinical experimentation. The 
amount of basic animal toxicology that we have at our disposal to 
design clinical research will have a profound effect on what 
research is done and how it is done, and of course, on the ration¬ 
ale for approaching a particular experimental design. 

The discipline that I would like to discuss is epidemiology. 
Most people think that epidemiology is not really a discipline, 
that it is a state of mind with which you approach a problem. But 
epidemiology is important because it is closely related to clini¬ 
cal research, and it deals with the species of interest, human 
beings. 

Epidemiology differs from clinical research in that it lacks 
two of the overriding characteristics included in the definition 
of clinical research. In epidemiology the subject is not mani¬ 
pulated. As a matter of fact, in epidemiology you do everything 
you can to avoid interfering with the normal behavior of your 
subject. Epidemiologists are concerned about a kind of Heisenberg's 
principle of biology: anything you do to study your subjects in 
an epidemiologic study design will interfere with those measurements 
because you specifically do not want to intrude on your subjects' 
way of life, and you certainly do not want to manipulate their 
environment. 

I want to discuss briefly the interrelationship between 
©pi<i 0 iniology, clinical environmental research, and environmental 


73 


toxicology. In the latter discipline, we have an exquisite 
handle on the dose, and you can do anything you wish to the subjects 
because they are expendable, and they are available in large 
quantities of inbred strains. You get all kinds of very precious, 
very specific information from these animals, but we always have 
to deal with the problem of extrapolating from these non-human 
species to what is going on in people. We know that there is 
often a great leap in extrapolating from animal data to the human 
situation. 

In epidemiology, we take advantage of the fact that we are 
studying humans, but we have only an imperfect idea of what the 
dose or what the extent of environmental stress is. There are 
just a few parameters that we can measure, and most of them with 
less than satisfactory precision. 

Taken together all three disciplines give us the coherent 
database from which we move toward regulatory action. With these 
interrelationships and strengths and weaknesses of the various 
approaches in mind, I would like to focus more on the discussion 
of the rationale of designing human experimentation to study the 
effects of environmental agents. 

LOGISTICS CONSTRAINTS 

I think it is important and absolutely necessary to take into 
consideration logistic constraints. I have to face the fact that 
I have only three sets of resources to work with: people, money, 
and time. I cannot control the third resource, but given the 
objective that targeted research has to be relevant to social 
questions, you must decide how to go about choosing the right 
question and answering that question with the resources at hand. 

A laboratory may require $10,000 a day to operate. You have a 
through-put of so many human subjects in a reasonable experimental 
paradigm per unit of time, so you have to very carefully decide 
how to use these scarce resources to address the question you are 
trying to answer. 

That is an integral part of the rationale of experimental 
design. I could come up with many experimental designs that would 
be appropriate, that would be scientifically meritorious, that 
would supply answers to the questions in an intellectually satisfy¬ 
ing way. But we do not have the luxury of pursuing research questions 
in that particular way. We have to look at the end points, the 
criteria for subject selection, to make certain that when we begin 
a five-day study that all of the subjects will participate for 
five full days, because the data each day are really quite ex¬ 
pensive. These elements in the rationale of the study design are 
more important than we scientists like to admit. In developing a 

74 


J 


rationale for an experimental design, it is important to have a 
statistical design that is highly parsimonious. 

I will give an example that will illustrate several points 
with respect to subject selection, range of susceptibility, and a 
few other points. The best example I can give is one having to do 
with carbon monoxide research because it is very simple. 

The carbon monoxide experiment was based on what we knew we 
could do, in view of some of the material constraints. It was 
based on what we knew carbon monoxide should do to people, and on 
the fact that we had an ambient air quality standard for carbon 
monoxide that was rather low. The automotive industry said the 
standard was irrationally low, but there was no real basis for 
their statement. 

I discussed with a colleague what test he thought we ought to 
conduct to study the effect of carbon monoxide on a particular 
human function. Historically the effects of carbon monoxide on 
the central nervous system had been the focus of research. My 
colleague was a cardiologist who knew about exercise stress testing 
and exercise electrocardiology. He said that the myocardium does 
not function very well during relative hypoxia. As a matter of 
fact, the blood leaving the myocardium has a partial pressure of 
oxygen, a PO^ of 25 millimeters of mercury, which is as low as it 
ever gets at rest. It does not get any lower at exercise. So, if 
you do something to interfere with oxygen delivery to the myo¬ 
cardium, you almost expect a priori to be able to measure some 
effect. We could measure something going on in the myocardium at 
relatively low levels of carbon monoxide. Here is how we did the 
experiment. We had people get on a treadmill and do an exercise 
ECG before they were subjected to a standard dose of carbon monoxide. 
One of the nice things about this test is that we can measure 
carboxyhemoglobin in the circulating blood, so we have an accurate 
estimate of the body burden of this environmental agent. We do 
not even have to depend on ambient air measurements, we just 
measure carboxyhemoglobin in the blood. We gave the subjects a 
certain amount of carbon monoxide to breathe, and we measured the 
carboxyhemoglobin again, and then we had them go on the treadmill 
again, and we looked at the electrocardiogram. 

In young, healthy adult males, who were the least susceptible 
because they should have the healthiest myocardium, we did not see 
any changes in the electrocardiogram. We saw changes in heart 
rate at various levels of activity. There was a price paid for 
the carbon monoxide load, but it did not show up in that particular 
objective parameter when we looked at the electrocardiogram. 


75 



Then we postulated that a cohort of men whose mean age was 45 
instead of 20 should include a few individuals who had preclinical 
ischemic heart disease, and that they should show some changes 
during the same experimental design. We tested that hypothesis 
and found that our presumption was true, that there were a certain 
number that changed their Minnesota code during the course of the 
experiment. We postulated that if this were true, then people who 
have well-defined, stable angina pectoris, people who have well- 
characterized coronary artery disease, ought to be much more 
sensitive to carbon monoxide. We tested that hypothesis, and it 
was valid. This is an oversimplified presentation of this particular 
set of experiments, but it serves as an example of logical progres¬ 
sion of hypothesis testing with the results of each experiment 
influencing the design of the subsequent one. 

HISTORICAL ANTECEDENTS OF CLINICAL RESEARCH 

Clinical research has been around for a long time in one form 
or another, only recently have scientists in general, not just 
physicians, begun to focus on man's relationship to his environ¬ 
ment. I believe that the Harvard Fatigue Lab of the mid-1920's 
represents the keystone of clinical environmental research. The 
Harvard Fatigue Lab was housed in the Harvard School of Business 
because the people who were interested in setting up the lab 
wanted to investigate "the adaptation of the normal individual to 
industry." 

There was a certain amount of social responsibility in industry 
at that time, and, as I read it, a hard-nosed desire to find out 
how you could maximize human productivity under certain environ¬ 
mental conditions, i.e., industrial conditions. 

The techniques, the attitude, and the rationale for environ¬ 
mental human clinical research were established by the investi¬ 
gators in the Harvard Fatigue Lab around 1927. The 20-year life 
of that institution takes us just past World War II. Interest¬ 
ingly enough, many of the alumni of the Harvard Fatigue Lab are 
active in clinical environmental research today. They moved on 
during the course of World War II to broaden their perspectives, 
and have led into what we have been doing for the last decade in 
clinical environmental research. These investigators became 
involved in cold and heat stress experimentation because of military 
operations under those conditions. Of course, the human element 
was the salient element of all that research—altitude physiology, 
dividing physiology, and submarine physiology, as examples. 

A modern corollary of that research is now being conducted in 
the hyperbaric chamber at Duke University. Because of the quest 
for new energy sources, investigators are studying ways man can 


76 


adapt to 1,000 feet of sea water so that oil may be extracted from 
the North Sea and other places. 

We are not alone in developing a rationale for clinical 
environmental research. We can rely on a number of years of high- 
level investigator or research scientist history to help us develop 
the rationale for clinical environmental research. 

FURTHER CONSIDERATIONS IN DEVELOPING A RATIONALE 

We must consider three further characteristics when develop¬ 
ing our design rationale. The first characteristic is subject 
selection. What is the rationale of subject selection? Perhaps 
because most of my earlier research work was with animals, I 
regret not being able to deal with nice inbred strains of mice 
when I am conducting human experimentation. Because of that, I 
suppose, I sometimes err in the direction of trying to design 
clinical experiments where I have a very homogenous population. I 
try to control as many of the covariants within the population as 
I possibly can, to minimize both inter- and intra-subject variance. 

The globe is not populated with 20-year-old robust Caucasian 
males who happen to be students at the University of North Carolina. 
Many inter-subject characteristics must be taken into consider¬ 
ation—ethnicity, race, and geography, to name a few. There are 
differences in cardiovascular performance and pulmonary per¬ 
formance, and there are probably profound differences in metabolic 
characteristics that we are just now learning to measure. What is 
true for our experimental subjects may not be quite true for the 
population at large. However, I think tests have to be based on a 
highly homogeneous population so as to minimize the inter-subject 
variance. 

My tendency as a first step is to try to identify all of the 
characteristics I can possibly measure in the subjects, and specific¬ 
ally select for or against those characteristics. In this way, I 
achieve as homogeneous a population as possible, albeit an artifical 
one. Using the information from the first step, I inject that 
information into the rationale for the succeeding experiments that 
we do, changing the characteristics of subject selection as I 
pointed out in the carbon monoxide experiments. 

The second characteristic to consider in developing a rationale 
is dose selection. Dose in the usual sense of the word is the 
amount or level of ©nvironmental stress, or the quantification of 
the environmental agent that will be used in the experiment. 

There is a bit of circular logic involved in how you decide what 
is going to happen with respect to your dose selection. At the 
minimum, we like to make some statistical statements about dose 


77 


selection and relevance because we are conducting the research for 
a specific reason. 

The third characteristic that must be considered in develop¬ 
ing a rationale for clinical experimentation is the selection of 
end points. As I indicated earlier, a cardiologist will not worry 
about evoked potentials, and a neurophysiologist does not care 
much about stroke volume. The person who designs research in 
clinical environmental medicine has to take several backward steps 
to look at what is known about the biology of the environmental 
agents he is studying. He must design experiments that are con¬ 
strained by staff and budget, and take advantage of an exposure 
situation to explore a variety of end points that are judged to be 
the most relevant biologically, and the most likely to yield 
important information. 

In summary, the rationale for designing clinical environ¬ 
mental research is multifaceted, and has to do with research 
objectives and available resources. Most importantly, because 
both the objectives for the research and the resources that are 
available are determined by the questions that society asks, the 
rationale has to strive diligently to maintain a high degree of 
relevance to the social questions that are being posed. 


78 


Discussion Summary 


The issue was raised whether experimental scientists should 
concentrate on anticipating and solving problems, rather than 
waiting for problems to ccxne up and then solving them. Partici¬ 
pants noted that some scientists currently operate according to 
the former procedure. For example, scientists have been success¬ 
ful in using biomathematical engineering to study the possible 
effects of certain pollutants. 

However, investigators said that they do not always have the 
resources to design and conduct what would be considered antici¬ 
patory studies. In addition, many of the topics chosen for study 
are questions that are formally posed to the EPA by Congress and 
that are important to the public (e.g., how safe is our environ¬ 
ment?) Thus, the investigator has a limited amount of time in 
which to conduct anticipatory studies. 

Participants also discussed the drawbacks in conducting 
experiments in a clinical rather than a natural setting. Is a 
clinically manipulated environment representative of what goes on 
in the natural environment? Discussants considered the case where 
a group of factory women who, in a laboratory situation sweat less 
than men, were observed on the job to be producing as much sweat 
per hour as the males did in the clinical setting. Although this 
points up the fact that the way a subject reacts in the laboratory 
may not be the way he reacts in a natural environment, partici¬ 
pants pointed out that no matter what group of subjects you are 
working with, the investigator will always be faced with some form 
of bias. For example, the factory women who disproved the theory 
based on clinical research that women sweat less than men, in 
themselves are not representative of women in general. They are 
women who have chosen to work in a hot factory, who have chosen to 
participate in the study, and so forth. Thus, any test reactions, 
be they derived from a clinical or natural setting, are not 
necessarily representative of what occurs in the general population. 


79 


Finally, investigators discussed the need to allot adequate 
time to completely examine and answer a study question. Partici¬ 
pants felt that the Congress and EPA administrators appreciate the 
need to plan long-range targeted research, and that money may be 
set aside for anticipatory research. Anticipatory research is not 
research that investigators plan to conduct in the future; rather, 
it is research that will take many years to complete. 


80 


Subject Selection, Investigator Interactions, 
Informed Consent in Clinical and 
Environmental Research 

David A. Otto, Ph.D. 

U.S. Environmental Protection Agency 

Jeanne T. Hernandez 

Institute for Environmental Studies* 


A revolution is going on in psychology. A 
different image of man is being tried as a guide to 
research/ theory, and application. Over the years, 
theorists have conceptualized man as a machine; as 
an organism comparable to rats, pigeons, and monkeys; 
as a communication system; as an hydraulic system; 
as a servomechanism; as a computer—in short, he has 
been viewed by psychologists as an analogue of 
everything but what he is ; a person. Man is, indeed, 
like all those things; but first of all he is a free, 
intentional subject.^ 

—Sidney M. Jourard 

PHILOSOPHICAL PERSPECTIVES: BEHAVIORISM vs. HUMANISM 

During the past two decades a lively debate has ensued between 
the proponents of the humanistic and the behavioristic traditions 
in psychology and related disciplines in the social and clinical 
sciences. This debate is directly relevant to the conduct of 
human research, since many time-honored principles concerning the 
relationship of the subject and experimenter have been called in 
question. 


* University of North Carolina 


81 






Beneath the "sound and fury" of men like Sidney Jourard and 
B.F. Skinner lies the fundamental philosophical question of man's 
freedcan to behave in a non-deterministic, unpredictable manner. 
According to a strict behavioristic model (or Freudian model for 
that matter)/ man's behavior is entirely determined by either 
external environmental stimuli or unconscious inner motives and 
drives bubbling up from the depths of the psyche. Although Skinner 
and Freud may seem to be rather incompatible bedfellows, Skinnerian 
and Freudian theories are both highly deterministic with respect 
to human behavior: that is, both theories imply that human behavior 
can be predicted and, to some extent, controlled by the appropriate 
manipulation of internal or external stimulus conditions. 

This deterministic view of man conflicts rather strenuously 
with the traditional humanistic view of man as a rational being, 
possessed of a variety of constitutional freedoms, including the 
right to withdraw from any scientific investigation whenever the 
spirit moves. In fact, the humanistic revolution in social psycho¬ 
logy has spawned an entire field of research devoted to subject- 
investigator interactions.2,3 The implications of the humanistic 
revolution extend far beyond psychology, however, since the Federal 
Government has now imposed strict regulations in accordance with 
the National Research Act to safeguard the "free will" or voluntary 
nature of participation in all HEW-funded human research projects.'' 

In essence, these legal and ethical constraints are designed to 
preserve the freedoms essential to the humanist view and to deny 
the behavioral controls alleged to the opposing view. 

Requirements of the National Research Act are difficult, in 
some respects, to reconcile with scientific objectivity, as well as 
specific objectives of environmental research. Miller® has succintly 
summarized the dilemma: "The goals of meaningful scientific inquiry 
may be at odds with the value of treating man in a dignified and 
respectful manner." This paper will explore some of the potential 
conflicts among the elements of informed consent and the conduct 
of environment research. 

The traditional objective of human research is to determine the 
effect of some carefully controlled manipulation on behavior. In 
other words, we predict that some external stimulus (such as noise) 
or internal stimulus (such as food or drugs) will alter behavior in 
a systematic way. If we seriously entertain the notion that man 
behaves in a totally non-deterministic, unpredictable manner, then 
human research would be a waste of time. We can easily extract 
ourselves from this paradox by adopting a compromise philosophy 
wherein some behaviors are subject to external control, while other 
behaviors are mediated by internal volitional processes. Even the 
most extreme humanist would be unlikely to deny the effects on 


human behavior of heat, cold, sleep deprivation, or carbon mon¬ 
oxide poisoning. 


What is the consequence of man's tendency to behave unpredict- 
ably? The exercise of free will in the laboratory yields consider¬ 
able noise in the data which the humanist calls "individual dif¬ 
ferences" and the behaviorist calls "intersubject variability." 

At this point the two investigators rapidly part ccxnpany, for the 
humanist is concerned with enhancing individual differences, while 
the behaviorist seeks to minimize intersubject variability. The 
manner in which subjects are selected determines, to a large 
extent, how much heterogeneity or homogeneity the investigator may 
expect. After a decade of behavioral research, however, we can 
attest that the application of stringent criteria based on stand¬ 
ard personality and medical inventories, physicals, and interviews 
to secure "normal, healthy" populations has been remarkably unsuc¬ 
cessful in reducing intersubject variability. No matter how 
rigorously subjects are screened in preparation for human experi¬ 
ments, there is little hope of ever attaining a p\ire laboratory 
strain of Homo sapiens 1 

The problem of intersubject variability is particularly 
severe in clinical environmental research where the objective is 
to define the threshold level at which a given substance produces 
significant impairment in function. Threshold effects, by defi¬ 
nition, are "just noticeable differences." The challenge in this 
field is to minimize individual differences, regardless of the 
philosophical bias of the investigator. 

SELECTION OF A PROTOTYPE SUBJECT 

How do we go about selecting human subjects for environmental 
health effects studies? Subject recruitment, though seldom pursued 
as an independent profession, has evolved to an exacting science 
in Chapel Hill. Since the University constitutes the primary 
industry, the student population is the major, if somewhat transient, 
source of subjects. That is, the normal, healthy, red-blooded 
collegian represents our closest approximation to a standardized 
Iciboratory animal. 

One might object at this point that our choice of "prototype 
man" is not particularly representative of the larger population 
to whom we wish to generalize our findings. Dr. Shy, for in¬ 
stance, argued at this symposium for the use of specific clinical 
populations considered to be unusually sensitive or susceptible to 
certain environmental insults. The rationale for using healthy 
young adults is that any functional impairments observed can be 
inferred to be more severe in susceptible populations. The prob¬ 
ability of observing effects attributable to low level exposure 


83 









may be artificially low in healthy young adults leading to Type II 
errors of statistical interpretation. That is, we may conclude 
that substance "X" produces no deleterious effects in the general 
population when, in fact, the same exposure may actually produce a 
functional impairment in an older or less healthy population. The 
risk factor, however, is correspondingly lower in healthy young 
adults than other populations. 

How do we define our standard subject? Prior to initiating 
any experiment, the principal investigator provides the recruit¬ 
ment staff with a specific list of criteria. I will quickly 
review the criteria used in selecting subjects for recent neuro- 
behavioral and physiological studies of environmental insult. In 
general, the criteria for selection of subjects to participate in 
studies which involve at least a marginal health risk are consider¬ 
ably more stringent than the criteria used in other studies which 
do not entail any health risk. The monetary inducements also vary 
relative to the associated risks or disccxnforts such as repeated 
blood draws. 

Ethical considerations preclude the exposure to risk of 
children, minors, or any other population that cannot provide 
informed consent. Current studies are limited to adults aged 18- 
40, although middle-aged and elderly sxibjects have been used in 
previous studies of the effects of CO on the onset of angina 
pectoris.® 

For pragmatic reasons, we have limited research to adult 
males. The potential danger of toxicant effects on the unborn 
fetus and the increased variability associated with hormonal 
changes during the menstrual cycle are primary considerations. In 
order to preclude the possibility of fetal damage, women must be 
given a pregnancy test prior to each experimental session. Since 
the observed effects of environmental toxicants, particularly at 
low concentrations, tend to be extremely subtle, the physiological 
and psychological state of subjects must be maintained as constant 
as possible. Exposures would have to be carefully synchronized to 
specific times in the menstrual cycle of women subjects to control 
for hormonal variation. These problems are avoided by restricting 
experiments to males. 

This strategy can be problematic in the present climate of 
sexual equality. For example, three coeds once walked into our 
laboratory demanding equal time and equal pay. An ozone experi¬ 
ment was then in progress in a transparent plastic exposure chamber. 
The girls were invited to observe a subject who was pedaling a 
bicycle ergometer while stripped to the waist for ECG recording. 

When the girls were asked if they still wished to participate, two 
blushed and withdrew their request. The third coed, however. 


smiled and asked vdien she could begin. The Institutional Review 
Committee, however, had not authorized us to expose females to 
ozone! 

The variable of race, like sex, raises ethical and pragmatic 
difficulties. Ewing et al./ for instance, have shown that blacks, 
orientals, and whites are differentially tolerant to the effects 
of alcohol. There is reason, therefore, to expect differential 
racial responsivity to environmental stressors such as carbon 
monoxide which is also considered to be a CNS depressant. If a 
multi-racial population is studied, a sufficiently large sample 
from each racial group is required to statistically evaluate 
possible racial differences. The usual practice (which could 
easily be construed as discriminatory) is to use subjects of a 
single race in order to eliminate this source of variability from 
the data. One strategy to avoid statistical and ethical conflicts 
is to restrict subjects in an individual study to a single race, 
but to use different races in different studies. 

How do we define "psychological" normality? Prospective sub¬ 
jects complete the Minnesota Multiphasic Personality Inventory 
(MMPI) and must score below the 75th percentile, unless otherwise 
specified by the principal investigator, in order to participate 
in environmental studies. Scores on the MF scale are disregarded, 
since most college students score high on this scale. The MF 
scale reflects aesthetic interests more than the masculinity- 
feminity dimension for which it was originally intended. 

The use of the MMPI as a psychological screen is admittedly 
arbitrary, although the test is standarized and widely used. The 
MMPI is neither foolproof nor all inclusive. For instance, the 
standardized MMPI profile does not indicate if a prospective 
subject is claustrophobic. It is simpler to ask directly if the 
individual is afraid of staying in a closed room for a long time. 

Why should the environmental researcher be concerned about 
the psychological normality of prospective subjects? The need is 
readily apparent for physical examinations and careful scrutiny of 
the medical history of prospective subjects to minimize the possibil¬ 
ity of extreme physiological reactions to pollutant exposure. It 
is also necessary to assess the emotional stability of prospective 
subjects since prolonged confinement in a relatively small testing 
chamber and/or exposure to a substance that is presumed to have at 
least mildly toxic effects can induce considerable psychological 
or emotional stress, even in psychologically normal subjects. 
Individuals exhibiting any signs or history of psychological 
abnormality should not be used in environmental health effects 

studies. 


85 


The potential psychological risks inherent in any clinical 
environmental study are seldcm considered seriously by investi¬ 
gators and are rarely articulated to subjects during pre-experi¬ 
ment briefings. In many studies, this oversight represents a 
clear breech of informed consent! The measurement of pollutant 
effects on psychological dimensions such as mood, anxiety, or 
hostility has likewise been neglected and constitutes an important 
area for future study in clinical environmental research. 

Smokers have been excluded from experiments testing the 
effects of carbon monoxide, ozone, and sulfuric acid aerosol. 

This exclusion is particularly important where the test substance 
is expected to alter oxygen uptake or respiratory function. How 
long should prospective subjects have been non-smokers in order to 
ensure "normal" lung function? Our physicians have specified a 
minimum of 10 years in oxidant experiments, a requirement that has 
strained the resources of the recruitment staff on occasion. In 
essence, this requirement limits subjects in college-aged popu¬ 
lations to those who have never smoked tobacco. 

Should the same criteria apply to marijuana smokers? In 
practice, a double standard is applied in the case of "pot" verus 
"tobacco" smoking. Investigators have adopted a much more tolerant 
attitude toward the occasional marijuana smoker than to the occasion¬ 
al tobacco smoker. At least half of our undegraduate recruits 
admit to the occasional use of pot, and the percentage is probably 
much higher. Why the double standard? In this case, scientific 
objectivity has been sacrificed to humanistic (and pragmatic) 
considerations. 

Other criteria used in subject selection include limitations 
on the use of stimulant beverages. Subjects should not have 
consumed more than two cups of coffee, tea, or coca-cola, or any 
other liquid stimulant within one hour of the start of the experi¬ 
ment. In addition, subjects cannot have consumed more than the 
following limits of alcohol within the 24 hours preceding the 
experiment (these limits vary for different experiments): in 
neuro-physiological experiments, the limit is 24 ounces of beer, 
or approximately two cans, within 24 hours of the test; 12 ounces 
of wine, or approximately two glasses; three ounces of hard liquor, 
two shots of whiskey, rum, or vodka, and so on. 

Furthermore, the subject cannot take any drugs, prescribed or 
otherwise, within 48 hours of the experiment. The term "drug" 
includes antibiotics, antihistamines, barbiturates, amphetamines, 
marijuana, heroin, cocaine, steroids, or other substances pre¬ 
scribed or self-administered for health, happiness, or habit. In 
some cases, the attending physician or psychologist may allow the 
subject to take aspirin, bufferin, or related compounds before the 
experiment. 


86 


To avoid the probletis of sleep deprivation or the converse 
during the experiment, subjects are required to have six to ten 
hours sleep during the previous night, and to sleep regularly 
within this normal range over the course of the experiment* 

Prior to exposure to any toxicants, prospective subjects 
complete an exhaustive medical history, the Duke Medical In¬ 
ventory, and are given a physical exam by EPA physicians. Any 
history of allergies or significant medical problens generally 
excludes candidates from participating in an experiment. 

Does the stringent selection process destine our experiments 
to produce negative findings or no effects? Perhaps it does. In 
other environmental laboratories in this county and in Europe 
there is much feeling that an investigator would get better results 
if he used a susceptible population. 

INVESTIGATOR ATTRIBUTES AND INTERACTIONS 

We have focussed thus far on attributes of prospective subjects 
which might influence performance in an environmental health 
effects study. Attributes of the experimenter can likewise affect 
the performance of subjects and possibly bias experimental results. 
This problem has been studied intensively by social psychologists 
during the past decade. Rosenthal^ reviews a wide range of bio¬ 
logical (e.g., sex, age, race) and psychosocial (e.g., anxiety, 
hostility-warmth, authoritarianism) attributes of the experimenter 
which affect subject behavior. For instance, college-aged subjects 
tend to cooperate better with experimenters of their own age and 
race, but of the opposite sex. The simple effects of biological 
variables, however, can be counterbalanced by or interact with a 
multitude of psychosocial variables. An experimenter perceived to 
be anxious, hostile, or rigidly authoritarian will elicit less 
cooperation from subjects than an experimenter perceived to be 
confident, warm, or tolerant. 

These observations may seem banal, but researchers seldom 
consider such obvious subject-experimenter interactive effects in 
the design of a study or the analysis of data. Let us consider a 
hypothetical example. The objective of a proposed study is to de¬ 
termine the effect of low level oxidant exposure on treadmill en¬ 
durance in healthy young adult males. Experimenter A is an at¬ 
tractive, congenial young woman, and experimenter B is a quiet, 
slightly over—weight, middle-aged man. Which experimenter is 
likely to achieve better rapport with subjects? And how might 
subject-experimenter interactions affect the results of the study? 

Based on age and sex factors, we can predict that subjects 
will probably establish better rapport with the female than with 


87 


the male experimenter. In terms of performance, we can also 
predict that subjects will probably exhibit greater treadmill 
endurance for the female than male experimenter. The objective of 
the experiment, however, is not to enhance subject-experimenter 
rapport or treadmill performance, but to impartially determine the 
effect of oxidant exposure on treadmill endurance. If we wish to 
minimize the effects of experimenter attributes on performance, we 
would probably obtain less biased results from the middle-aged 
male! 


This example, furthermore, confronts us with a basic dilemma 
in clinical environmental research. Subject-experimenter inter¬ 
action is but one of many motivational variables which can affect 
the performance of subjects. Since the effects of low level 
toxicant exposure are likely to be subtle, motivational variables 
of this kind can easily mask the effect of exposure and lead to 
false negative results. On the other hand, the current Zeitgeist 
of human research, mandated in many respects now by federal regu¬ 
lations, is to treat subjects in a warm, open, humanistic manner. 
Subjects are persons, not guinea pigs! The challenge is to strike 
a balance between humanistic concerns and scientific objectivity! 

SUBJECT EXPECTANCIES, INFORMED CONSENT, AND SCIENTIFIC OBJECTIVITY 

I would like to explore one final aspect of siobject-investi- 
gator interaction that is known to have considerable effect on 
subject performance. What a subject expects to do or to happen in 
an experiment is an important determinant of his behavior in that 
experiment. Psychologists frequently refer to the expectancy 
variable as experimental or instructional "set." Physicians are 
familiar with this phenomenon as the "placebo effect." 

Appropriate control conditions must be included in experi¬ 
ments to differentiate expectancy effects from the effects of 
other variables that the experiment is designed to test. Drug 
studies, for instance, usually include a placebo condition in 
which subjects unknowingly receive a substance that does not 
contain the active ingredients of the drug being tested. Subjects 
receiving the "placebo" are deceived by the investigator in order 
to distinguish the genuine effects of drug "X" from the spurious, 
but often therapeutic, effects of subject expectancy. 

Expectancy effects can be controlled or minimized by other 
means. A method frequently used in the past was simply to conceal 
frcxn subjects the true objectives of the study or the hypotheses 
under test. Although the necessity for placebo conditions in drug 
studies is generally accepted, the use of deceptive procedures in 
other types of human research is rarely sanctioned any longer by 
institutional review boards. Full disclosure to subjects of the 


88 








objectives, procedures, discomforts, and risks constitute elements 
of informed consent which must now be obtained prior to partici¬ 
pation in any experiment. 

We are faced again with a dilemma in which ethical consider¬ 
ations and human rights may be at odds with scientific object¬ 
ivity. A priori disclosure to subjects of the anticipated effects 
of an experimental manipulation will obviously shape expectancies 
and bias responses. Let's consider a specific example: an experi¬ 
menter warns subjects that ozone exposure may cause temporary 
irritation of the eyes, throat, and chest; headache; and nausea. 

The experimenter cannot obtain a valid, unbiased measure of the 
frequency or severity of these symptoms following exposure. Nor 
can single- or double-blind control procedures be effectively 
employed since the presence of ozone is readily apparent to both 
subject and investigator. 

THE ELEMENT OF RISK IN CLINICAL ENVIRONMENTAL RESEARCH 

Specification of risk in environmental research also raises 
contradictions. How can we adequately inform subjects of the 
anticipated risks of expos\ire when one of the basic objectives of 
environmental health effects studies is to determine empirically 
what those risks are? On the other hand, we have no legal right 
to expose humans to any conditions that might significantly impair 
any vital function for an extended period of time. The margin of 
risk in any proposed human study must be extremely small, and any 
functional impairments produced by exposure must be transient and 
completely reversible. The enigma of clinical enviromental research, 
therefore, is how to determine the threshold of human risk to 
pollutant exposure without exposing humans to significant risk! 

In conclusion, federal regulations to protect the rights of 
human subjects severely limit the scope and conduct of clinical 
environmental research. The U.S. Environmental Protection Agency 
has been mandated by Congress to determine the risk to human 
health of a wide gamut of potentially toxic substances. The 
Department of Health, Education, and Welfare has likewise been 
mandated to protect the rights of human subjects. Unfortunately, 
the two mandates are not entirely congruent. Clinical environ¬ 
mental researchers must carefully tread the tightrope between 
these opposing mandates since the achievement of meaningful environ¬ 
mental quality standards hangs in the balance. 


89 



REFERENCES 


1. Jourard, S.M.: Disclosing Man to Himself. Litton Educational 
Publishing, New York, 1968. 

2. Rosenthal, R.: Experimenter Effects in Behavioral Research. 

John Wiley, New York, 1976. 

3. Rosenthal, R., and Rosnow, R.L.: The Volunteer Subject. John 
Wiley, New York, 1975. 

4. PL 93-348 implemented in accordance with the Code of Federal 
Regulations (45 CFR 46). 

5. Miller, A.G. (ed.): The Social Psychology of Psychological 
Research. The Free Press (McMillan), New York, 1972, p. 76. 

6. Anderson, E.W., et al.: Effect of low-level carbon monoxide 
exposure on onset and duration of angina pectoris: A study in 
ten patients with ischemic heart disease. Ann. Intern. Med. 
79:46-50, 1973. 

7. Ewing, J.A., Rouse, B.A., and Pellizarri, E.D.: Alcohol 
sensitivity and ethnic background. Am. J. Psychiat. 131:2, 1974. 


90 




Discussion Summary 


Participants discussed the importance of physical criteria in 
screening subjects; for example, what is the subject's aerobic 
capacity? Is the subject under or overweight? It was agreed that 
all subjects should undergo a rigorous physical examination before 
being allowed to participate in an experiment. It was further 
noted that some investigators simplify the process of finding 
healthy subjects for each experiment by forming subject pools from 
which to draw subjects as they are needed. 

Discussants also questioned how the investigator verifies the 
information the subject tells him. For example, how can the 
investigator be sure that a particular subject has never smoked a 
cigarette? Or that the subject didn't drink four glasses of wine 
the night before the experiment? Some investigators said they 
take subjects at their word. Others devise series of questions 
designed to elicit the truth from prospective subjects. 

Participants discussed methods of screening middle-aged and 
elderly subjects. In general, the screening method depends on the 
purpose of the study. For example, middle-aged persons are regarded 
as particularly sensitive to pollutants. Therefore, any tests 
involving pollutants would necessitate testing to ensure that none 
of the middle-aged subjects are over-sensitive to pollutants. 

Discussants agreed that all subjects, regardless of age, must 
be carefully tested, perhaps more intensively than they are at 
present, to ensure the subjects' safety. 

Assuming that there is no such thing as a "normal" man, 
discussants questioned how investigators arrive at a set of criteria 
to select subjects for specific experiments. The process of 
determining a set of criteria was described as "evolutionary." 

Thus, over the span of a number of tests, investigators gradually 


91 


develop a list of variants that have proved to be important in 
choosing subjects and preparing them for an experiment. For 
example, after conducting a number of tests, investigators deter¬ 
mined that a lack of sleep would distort a subject's test responses. 
Thus, subjects are required to sleep a certain number of hours on 
the night before the experiment. 

In some instances, criteria are tailored to specific experi¬ 
ments. For example, in tests involving respiratory measures, 
investigators would want to know whether a subject has a history 
of lung disorders. 

Some discussants indicated that they have used female sub¬ 
jects in their experiments with no problems. Other participants 
urged the use of healthy middle-aged and elderly subjects in 
experiments. 

Finally, one participant suggested a randomization of the 
double blind procedure, to avoid biasing a subject's test response 
by telling him at the start of the experiment what effects to 
expect. A subject would still know what test effects to expect, 
but he would not know on what day he would actually be exposed to 
the test substance. 

Some participants felt that if a subject was sufficiently 
susceptible to the powers of suggestion, it would not matter 
whether or not he was exposed to the test substance because he 
would react the same in either situation. In addition, partici¬ 
pants said that if the effect of the exposure is strong enough, 
responses induced by suggestion would not be critical. 


92 


Acute Versus Chronic Studies 


David Bates, M.D. 

University of British Columbia 
Vancouver, Canada 


Acute studies are those that involve an exposure of less than 
12 hours duration in a controlled environment, with observations 
of changes in physiological function. Recent concern over air 
pollution has undoubtedly precipitated an increase of interest in 
what these studies may reveal and also in their limitations. If my 
memory serves me right, in the 1890's, J.S. Haldane graphically 
demonstrated the unique importance and value of human studies when 
he breathed carbon monoxide when exercising and noted the effects 
on himself. I recall that the experiment ended when he fell off the 
bicycle ergometer. Haldane noted that these experiments gave him an 
insight into the physiological effects of progressive carbon monoxide 
intoxication, which he couldn't possibly have gained from animal 
observations. 

I believe that a few years from now, historians will be rather 
surprised at how slowly the development of acute studies in a 
controlled environment occurred. After all, the major pollution 
episodes took place more than 20 years ago, and it is still possible 
to go into the medical literature looking for a specific answer to 
an important question and find that very little experimentation has 
been done. In the case of sulphur dioxide, for instance, we do not 
know precisely the range of individual variability, or the association 
of a high sensitivity to sulphur dioxide as measured by changes in 
airway resistance, to other thresholds of sensitivity as measured 


93 


by the inhalation of mecholyl or histamine. We do not have a 
precise quantitation of the effect of mouth or nose breathing 
in an atmosphere of SO 2 on the development of changes in airway 
resistance. We do not know whether a two-hour exposure on one day 
will influence the response in a given individual in succeeding 
days. We do not know whether the acute response to sulphur 
dioxide is any different in individuals who live and work in 
relatively high concentrations of this gas and, in general, we 
have very little acute laboratory data to put alongside our 
guesses of its chronic effects. I mention these obvious outstand¬ 
ing questions to indicate that it should be a matter of surprise 
to us that one can ask these and find that we do not have reliable 
laboratory data to answer them, when we have known for a long time 
that sulphur dioxide is one of the principal constituents of the 
older type of air pollution episode. 

ACUTE EXPOSURES 

In general, we require that acute studies mimic actual 
exposure conditions and we try to isolate independent variables. 

This may be a difficult task since exercise alone without any 
environmental contaminants will cause a decline in expiratory 
flow rate or an increase in respiratory resistance in asthmatics. 

In the case of oxides of nitrogen, we have recently been given 
the results of an acute exposure experiment in asthmatics,^ 
which indicates that this gas in relatively low concentration 
enhances the response of the asthmatic to a subsequent challenge 
by mecholyl. This is a good example of the value of such acute 
experiments. It has been suggested that an exacerbation of 
spontaneously occurring asthma is one of the earlier effects of 
oxidant pollution. The acute experiments on ozone have undoubtedly 
helped us to define better the levels at which significant airway 
obstruction develops, and have, in addition, given us an important 
idea of individual variation. We have also found evidence, I 
think for the first time, that the response to this gas, when 
acutely encountered, may be lower in those who customarily live 
in an area of relatively high oxidant pollution. 

Taken together, these and many other studies give us a good 
idea of the kind of information that such acute experiments can 
provide. I would tabulate these advantages as follows: 

• The determination of the earliest measurable physiological 
or biochemical effect. 

• The study of individual variation and the modification 
of effects by other pollutants or by other factors 
such as exercise or heat. 


94 


The study of individual adaptation or modification of a 
response by previous exposure. 


• The study of the mechanism of action of the gas concerned 
and the relationship between early symptoms and changes 
in function. 

Acute human studies are also important because they form a 
part of the total evidence of the effect of a pollutant, fitting 
between animal data and chronic exposure studies. It is when data 

from all three sectors begin to show some general concordance that 

we begin to be confident of the emerging picture. I do not 

believe that that picture can be satisfactorily completed unless 
acute human exposure data are made available. 

As I have mentioned earlier, the surprise to me is that such 
acute studies have taken such a long time to be developed. I 
haven t much doubt that we still have a great deal to learn from 
such studies and I think that it is very important that the present 
tendency to discount or to make difficult such human studies 
should not discourage investigators from trying to undertake them. 

OCCUPATIONAL EXPOSURE 

In listening to a discussion on the precautions that must be 
taken by investigators to ensure that volunteers fully understand 
the nature of the risks involved in such experiments, it occurred 
to me to wonder whether, or how often, we apply the same standards 
in relation to occupational exposure. Are the hazards of asbestos 
discussed with those who are going to handle the material? Are 
workers in the rubber tire industry told about the increased 
incidence of bladder cancer in workers in some sections of that 
industry? Interestingly enough, a recent Royal Commission in 
Ontario ^ has recommended that because the radiation hazard of 
uranium was not explained to the miners in advance, and they were 
not told of the hazard of this exposure when paired with cigarette 
smoking, all men in that occupation who develop lung cancer should 
be considered eligible for full compensation. 

I have a feeling that some people are unenthusiastic about 
acute human studies because of a particular perspective on the 
problems of decision-making. Their argument would run somewhat 
like this: "I am not interested in the level of a gas sufficient 
to cause reversible bronchospasm in a normal individual, unless 
you are prepared to tell me that reversible bronchospasm is a 
disease." I think this argument requires discussion. I note that 
the World Health Organization report on atmospheric pollutants 
laid down four categories of pollutant levels, which were designed 


95 


to be helpful to those considering exposure guidelines. Their 
Level III reads as follows: 

"Concentrations and exposure times at and above 
which there is likely to be impairment of vital 
physiological functions or changes that may lead 
to chronic disease or shortening of life." 

This is a convenient definition since obviously a concentra¬ 
tion of the gas sufficient to cause acute airway obstruction is 
causing impairment of a vital physiological function. We there¬ 
fore do not have to distinguish between that effect and the 
possibility of causation of a chronic disease in setting a pollu¬ 
tant level within the category of Level III. 

I think that this objection to acute studies is really quite 
illusory. We are very likely to make a decision that concentra¬ 
tions of gases high enough to cause easily measurable impairment 
of airflow in normal people is not an environment that we should 
accept as strictly necessary or desirable. Those who would argue 
that reversible bronchospasm is not a "disease" are presumably 
prepared to argue that reversible bronchospasm can be safely 
ignored in the setting of ambient standards. As far as I am 
concerned, in that discussion the burden of proof rests with them 
to demonstrate that repetitive bronchospasm of that kind is not 
producing adverse effects, before we should accept that the 
environment that produces it should be considered acceptable for 
the general public. I do not feel therefore that this objection 
to acute studies, which is essentially an attitude of "we won't 
know what to do with the results when we get them," is one that 
should play much part in determining their appropriateness. 

The other objections to acute studies have to do with the 
necessary artificiality of the protocol. This is unavoidable if 
you want to eliminate a good many variables present in the normal 
outdoor environment. But it may be a valid objection that ethical 
considerations prevent especially sensitive people from being 
studied and preclude studies on those whose cardio-pulmonary 
status is already compromised. I have already mentioned a recent 
acute study using nitrogen dioxide at very low concentration in 
which known asthmatics participated, so this objection is not 
absolute. However, we must recognize the fact that acute exposure 
studies are very difficult to do on some of the population groups 
we may want to protect. The answer here would be to get as clear 
a definition of effect in relatively healthy normal people in the 
first instance, and then be prepared to protect others by insisting 
on some built-in safety factor when determining safe levels for a 
population. 


96 


CHRONIC EXPOSURES 


In my opinion, chronic experiments on pollutants are not 
really possible in the laboratory. I do not have a precise 
definition of chronic, but exposures lasting weeks or months do 
not seem feasible in terms of human experimentation, and there¬ 
fore, the only "laboratory" that can be used for such studies is 
one in which individuals are already exposed to higher levels of 
some materials than are the rest of us. These chronic exposures 
give us an opportunity to study comparative morbidity in different 
occupational settings, and without doubt they are helpful in 
defining the upper level of exposure permissibility. 

In the case of oxides of nitrogen, the studies of tunnel 
workers in New York exposed to relatively high concentrations of 
automobile exhaust indicated a probable upper level beyond which 
overt and obvious respiratory consequences would be detectable. 

In the case of sulphur dioxide, a recent study of smelter workers 
exposed chronically and intermittently to less than five parts per 
million of S 02 **will prove very valuable in indicating the conse¬ 
quences of exposure to sulphur dioxide at that concentration on 
ventilatory function. In the case of ozone, it would be helpful 
to have detailed knowledge of any deterioration or lack of it in 
welders or in air crew who are intermittently exposed to ozone 
levels high enough to cause characteristic symptomatology. The 
recent reports of acute ozone symptoms occurring in some flights 
from the United States to Alaska indicate the kind of opportunity 
that could be taken advantage of once the actual levels of ozone 
exposure were accurately known. 

In the case of carbon monoxide, there are population groups 
exposed to high concentrations who may well be used to provide 
information on its long-term effects. Because of the common 
dissociation between those involved in environmental work and 
those involved in occupational medicine, there is a need for 
bridging the gap between the two disciplines, and there is 
certainly good use to be made of data secured in one kind of 
experiment in relation to decisions made in another sector. 

There are valid objections to this kind of chronic study that 
are relevant to decision-making, particularly when they apply in 
the occupational setting. The work force that is exposed to 
these materials is not the same as the general public. It is 
sometimes argued that, with a specially selected work force and 
careful medical surveillance, higher exposure levels may be toler¬ 
ated than you would allow for the population at large. But such 
a point of view often takes for granted the existence of detailed 
and precise medical surveillance, which, in my experience, is not 


97 


often a reality. In spite of these objections/ every opportunity 
must be taken to make measurements of individuals breathing higher 
concentrations of some materials than the rest of us, and I cannot 
see anything wrong with that kind of scientific opportunism. 

The whole field of epidemiological study may be viewed as the 
logical way for us to begin to understand effects. In respect to 
carcinogenesis, of course, it is the only tool open to us except 
for laboratory testing of suspicious materials. 

STANDARD-SETTING 

Before I conclude, I wish to reflect on the relationship 
between all these modes of experimentation and decision-making on 
standards. It seems to me that it is the concordance of data that 
provides the most convincing case on which defense of any single 
number for human exposure can be successfully mounted. There are, 
however, some other considerations that I feel I should draw to 
your attention. 

First, in reading the voluminous and expanding literature on 
standard-setting, I think it is as well to remind ourselves that 
the essence of the standard-setting process is to be able to 
advance a hypothesis on the basis of the best information avail¬ 
able. The hypothesis may be simply that exposure of a normal 
population to not more than some level of a contaminant will not 
have any adverse effects on the physiological function of the 
individual, nor any long-term effects on his health. I would 
argue that this kind of hypothesis is not greatly different from 
the kind of hypothesis that scientists are constantly advancing in 
respect to laboratory experiments, and the deductions that may be 
drawn from them. There is sometimes a tendency to blur this 
essential similarity by arguing that in one case the scientist is 
dealing with "hard fact," and in other cases, the information is 
relatively soft. 

We can also recognize that it is quite easy to frame questions 
from the political sector that are beyond the scope of any kind of 
scientific experiment to answer in any precise way. However, what 
is being attempted in the standard-setting process is to look 
carefully at some hundreds of scientific papers and to distill 
from the accumulated data the best available hypothesis for protec¬ 
tion of the public. 

In that endeavor, both acute and chronic studies are neces¬ 
sary, and there doesn't seem to me to be any reason to favor one 
kind of study over the other, since they answer different kinds of 
questions and provide a different sort of information. What seems 


98 


to me to be indisputable is that both kinds of information are 
needed/ as is the information we get from animal toxicological 
studies, and one in no sense excludes the value of the other. The 
initial title I was given to address on this program perhaps 
suggested that there was some kind of competition between the two 
kinds of studies I have talked about, but this doesn't seem to me 
to be an appropriate attitude. What seems to me more necessary to 
emphasize is how little of this general work has been done in view 
of the obviously pressing nature of the questions that naturally 
arise from the man-made environmental deterioration to which most 
of us are exposed. 

Second, I feel that in the acute studies and, indeed, in some 
of the chronic ones, there is a special advantage in studying 
physicians. Our initial studies of 0.75 parts per million of 
ozone* were all done on physicians for several reasons. They 
could be presumed to understand fully the nature of the risk; 
they might be specially capable of recording early symptoms; and 
we felt we could rely on them to discontinue the exposure if 
untoward symptoms occurred. In some situations, therefore, there 
is a special merit in adopting that kind of protocol. In chronic 
studies too there are some advantages to studying physicians and 
you will remember that Dr. Richard Doll's original study on ciga¬ 
rette smoking and lung cancer was based on a prospective study of 
British doctors, partly because he expected that the diagnosis 
would be more accurate in them, and also because he hoped that he 
would have a lower dropout rate. 

Third, I think we should not only view our work as being 
necessitated by questions that society is insisting should be 
answered, we should accept the responsibility of generating the 
questions and of working towards knowledge that we can see is 
going to be needed, often in advance of any public appreciation 
that the questions are indeed important. It is important to 
preserve the opportunity for innovative research in advance of 
public opinion. 

In that connection I might end by telling the story of the 
encounter in the street at night between a slightly inebriated 
man who was circling around under a street lamp, and a helpful 
passerby who asked him what he was doing. "I have dropped my 
keys somewhere," the first man said, and the second joined him in 
looking for them. After a few seconds, the sscond man inquired, 
"Are you sure you dropped them here?" And the first man replied, 
"No, but this is where the light is." In reviewing our research 
effort, we must always make room for the important idea in a field 
not yet illuminated by the glare of public attention. 


99 


REFERENCES 


1. Orehek, J., Massari, J.P., Gayrard, P., Grimaud, C., and Charpin, 
J.: Effect of short-term, low-level nitrogen dioxide exposure on 
bronchial sensitivity of asthmatic patients. J. Clin. Invest . 

57: 301-307, 1976. 

2. Report of the Royal Commission on the Health and Safety of Workers 
in Mines. Province of Ontario, Toronto, Canada, 1976. 

3. Ayres, S.M., Evans, R. , Licht, D., Griesbach, J., Reimold, F., 
Ferrand, E.F., and Criscitiello, A.; Health effects of exposure 
to high concentrations of automotive exhaust. Arch. Env. Health 
27: 168-178, 1973. 

4. Smith, T.J., Peters, J.M., Reading, J.C., and Castle, C.H.: 
Pulmonary impairment from chronic exposure to sulfur dioxide in 
a smelter. Amer. Rev. Resp. Pis . 116: 31-39, 1977. 

5. Bates, D.V., Bell, G.M., Burnham, C.D., Hazucha, M., Mantha, J., 
Pengelly, L.D., and Silverman, F.: Short-term effects of ozone 
on the lung. J. Appl. Physiol . 32: 176-181, 1972. 


100 






Discussion Summary 


Participants discussed the problem of distinguishing defense 
mechanisms from toxic responses in the lower dose acute studies. 
Whether or not they trigger reversible or irreversible changes, 
defense mechanisms cannot be equated with toxic responses. Some 
participants questioned the exact meaning of "toxic response." 

For example, sweating is a normal non-toxic response to heat, but 
excessive heat, even with the sweating response, can kill a person. 

Further discussion focused on the phenomenon of a repetitive 
stimulus that provokes a physiological response. Participants 
noted that evidence is mounting to indicate that a repetitive 
stimulus that causes a physiological response may produce long¬ 
term adverse effects. For example, a follow-up study of 18-month- 
old infants afflicted with bronchiolitis revealed that at ages 
seven to ten, these children showed compromised pulmonary function. 
Participants agreed on the need for more follow-up data and acute 
studies on repetitive stimuli. 

Participants also discussed the trend away from controlled 
experimental studies that last longer than twelve hours. Studies 
of this duration were not thought to be useful to the researcher 
for two reasons. First, most exposures occurring in the environ¬ 
ment are episodic; for example, an exposure to a pollutant. Thus, 
a study that exposes a subject to a pollutant for an extended time 
period would not be a valid model for an investigator. 

Second, studies that run longer than twelve hours are not 
long enough to be valid models for studying long-term effects. 

For example, if a researcher were interested in studying the 
effects of long-term exposure to sulfur dioxide, the appropriate 
study subject would be a smelter worker who had been exposed to 
the substance for the last five years. Thus, the experiment that 
lasts longer than twelve hours is usually too short or too long to 

be practicable. 


101 


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Role of Automatic Data Processing in 
Clinical Research 


Frank Starmer, Ph.D. 

Duke University Medicai Center 


When discussing automatic data processing in the setting of 
clinical research, it is helpful to have a sharp idea of what 
clinical research is. For this discussion, we will define clinical 
research as the activities associated with acquiring and transform¬ 
ing clinical or patient experiences into knowledge. This knowledge 
allows us then to predict or anticipate outcomes, given a character¬ 
ization of a patient and his surrounding environment. This knowl¬ 
edge of patient-environment interaction is thus helpful not only 
in establishing effective treatment, but also in developing policies 
for maintaining our surroundings that are compatible with a desired 
quality of life. 

The basic tool of the clinical investigator is the stimulus- 
response experiment. Experimental preparations are characterized, 
as well as the stimulus or change in environment with which the 
preparation exists. Certain signals representing function of the 
preparation are monitored over time and changes are detected. 

Because signals sometimes contain variations over space or time 
that seem unrelated to the experiment, a control study is usually 
carried out where the environment is standardized. Thus, changes 
in the monitored signals obtained from the experimental study are 
considered significant only when they exceed the changes observed 
in the control study. 


103 


SOFTWARE 


Data processing plays a number of roles in the support of 
clinical research as described above* First/ signals from patients 
or experimental subjects must be acquired. These signals usually 
contain much redundancy and therefore are not dealt with in their 
virgin form. The signals are first transformed into a set or 
sequence of primitive elements.^' ^These primitives are assumed 
to allow adequate description of the original signal. The 
representation of a signal by a sequence of primitives is called a 
message. As an example/ when dealing with the electrocardiogram 
we can choose several classes of primitives to construct a message. 
One class contains the characters P/ q_, r, s, t, _ where each 
character represents a certain feature. A message constructed 
from this set of primitives might appear as 

p_qrs_t __ 

Another class of primitives might be the set of integers where the 
integer selected is the amplitude of the signal at a point in 
time. ThuS/ the sequence 

1 2 3 2 1 0 0 -1 -2 -3 -3 -2 2 4 10 20 10 4 2 

-2-3-2-1000012321000 

is a message representing the same EKG signal/ but constructed 
from a different set of primitives. 

Many times these primitives can be detected automatically by 
a signal-processing computer. Such automatic signal processing is 
helpful. It reduces the time between signal acquisition and 
signal analysis/ as well as providing a high degree of consistency 
in the pattern recognition. 

Messages comprised of sequences of primitives describe the 
various facets of a clinical experiment. However/ to be useful/ 
features must be derived from messages and organized in a manner 
that is appropriate for data analysis. 

Data management is a second role where computing can provide 
considerable aid. The data management component of supporting 
clinical research consists of both deriving features from incoming 
messages and distributing messages/ message components/ and 
derived features to various user data files. The bulk of data 
management activities can be classified as file management and as 
such/ can be considered disjoint from both the data acquisition 
and data analysis activities. 


104 


Although feature recognition is not usually considered part 
of data management activities, I would submit that it, in fact, 
is. Feature extraction or recognition, such as computing heart 
rate from the EKG, many times does not need to occur in real time 
as does data acquisition. Therefore, it can and probably should 
be deferred to minimize the overhead during data acquisition. The 
plsce to put feature selection is in the activity that 
deals with message and file management, i.e., the data management 
activity. 


Another reason for considering feature extraction as part of 
data management is that it tends to be evolutionary in nature. 

For instance, during the early phase of an experiment, heart rate 
may be the only parameter thought to be of interest. However, as 
the experiments progress, it is observed that S-T segments really 
seem to reflect the stimulus and therefore should be analyzed. If 
the original data were represented in sufficient detail by primi¬ 
tives, then this new feature could be extracted from old studies 
without reacquiring the primary data. This activity is clearly 
data management. 

Data analysis is perhaps the most difficult area in the 
support of clinical research. Because data analysis tends to be 
evolutionary during the life cycle of a research project, the 
tools for supporting analysis must be flexible. It is here that 
the flexibility of a computer can be used to a considerable extent. 

Data analysis is the combination of selecting subsets of the 
original database, and analyzing selected variables within these 
subsets or comparing subsets. Since the degree of subsetting 
cannot be easily forecast, it is important to organize a data file 
in such a way that subsetting is easy. For this reason, a flat 
file or matrix file is a useful data structure.** The rows of the 
matrix represent instances of the research protocol (1 row = 1 
patient), while the columns represent the data values of various 
parameters. The matrix can be represented in either row order 
(direct file) or column order (transpose file). The transpose 
representation is most useful for subsetting, while the direct 
file is most useful for data analysis. 

In a computing system supporting data analysis, flexibility 
is achieved by avoiding the binding of variables in a user program 
directly to columns in the matrix. By interposing a dictionary 
that associates variable names with column positions between the 
user program and the data files in the matrix, the accessing 
program can avoid the need to know the exact location of variables 
in the file structure. Thus, adding or changing variables simpli¬ 
fies modifying dictionary entries, while the software driving the 


105 


data analysis remains unchanged. Program maintenance is minimized 
using such dictionary driven databases. 


HARDWARE 

The partitioning of research support activities into data 
acquisition, data management, and data analysis leads naturally to 
a distributed view of the hardware used to implement these activi¬ 
ties. In our own laboratory, we have developed the support soft¬ 
ware in such a way that the communication between data acquisition, 
data management, and data analysis is relatively clean and well- 
defined. A clean interface then makes it possible to support 
various components on a variety of hardware devices. For instance, 
while text based data entry (history, physical, etc.) is supported 
by the computer that primarily manages the database, some of the 
graphic data entry activity is supported by remotely located 
microprocessor based systems. In addition, while some data analysis 
is performed by the data management machinery, we also utilize the 
resources of our university computation center. 

The point of all this flexibility is to allow for the known 
unknown, that is, we all know that tomorrow we would like to 
improve some aspect of the experiment but we don't know exactly 
what. Decentralizing data acquisition in particular is very 
helpful in this regard. If a small micro or mini computer 
supports some phase of data acquisition, it can be changed without 
much involvement of other hardware/software functions, whereas 
centralizing this activity does not lead to easy change. Similarly, 
if the data management strategy is supported on a dedicated system, 
it too can be modified without much long-range effect. With 
machine costs dropping, such an approach appears viable. Task 
switching overhead is minimized at the cost of increased communi¬ 
cation cost between systems. It will certainly be interesting to 
watch the progress over the next few years. 

SUMMARY 

Automatic data processing can be used as a profitable adjunct 
in clinical research. When properly developed, ADP can increase 
the flexibility of data acquisition, data management, and data 
analysis over manual systems. It allows the investigator freedom 
of choice in the evolution of his experiment by holding open data 
interpretation and analysis options as long as possible. The 
complexity of today's experiments is great, and the manual tools 
in many cases are not adequate to deal with that complexity. 


106 


REFERENCES 


1. Horowitz, S.L.: A syntactic algorithm for peak detection in 
waveforms with application to cardiography. Comm. A.C.M. 18: 
281-285, 1975. 

2. Kirsch, R.A.: Computer determination of the constituent 
structure of biological images. Comp. Biomed. Res . 4:315-328, 
1971. 

3. Cox, J.R., Fozzard, H.A., Nolle, F.M., and Oliver, G.C.: Some 
data transformations useful in electrocardiography. ^ 
Computers in Biomedical Research. (Vol. 3) Academic Press, pp. 
181-206. 1969. 

4. Starmer, C.F., Rosati, R.A., and Simon, S.B.: Interactive 
acquisition and analysis of discrete data. Comp. Biomed. Res . 
5:505-514, 1972. 


107 







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Discussion Summary 


In a discussion of the computer operator's role in processing 
clinical data, participants said that the increased reliability on 
the operator to review complex records as they are processed 
increases the reliability of data analyses. This is true particu¬ 
larly in those instances where the computer program does not seem 
to be acting reliably or where extraneous signals are coming in. 
Participants said that in some cases, the computer operator is a 
laboratory clinician. 

Some of the discussants prefer to use an automatic data 
acquisition system that eliminates the necessity for operator 
interaction. Participants said this procedure ensures that an 
objective data base will be produced. These discussants felt that 
using operators in the data review process introduces an element 
of doubt as to the reliability of the resulting data base. 

Participants also discussed the role of automatic data 
processing in patient care. When the patient enters the hospital, 
an intern records his medical history and chief complaints on a 
check list form distributed by the data processing laboratory. 
Next, the laboratory determines whether the patient's data is 
accurate by checking the collected data against other hospital 
test results. If there is a discrepancy between the laboratory 
data and hospital test results, the patient is re-examined. 

Discussants said that automatic data processing improves the 
quality of patient data by double checking its accuracy. 


109 


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ENVIRONMENTAL AND PHYSICAL SAFETY 
CONSIDERATIONS IN HUMAN 
EXPOSURE FACILITIES 


Moderator: Russell Pimmel, Ph.D. 











Environmental Controls and Safeguards 


Morton Lippmann, Ph.D. 

Department of Environmental Medicine 
New York University Medical Center 


The test environment, and, in particular, the exposure atmos¬ 
phere, are of primary concern in controlled inhalation studies. 

There are many physical factors in the test environment that can 
affect the results of an experiment. Temperature, humidity, light 
and noise levels, and many other factors need to be stabilized, 
controlled, and described adequately. However, considering the 
focus of this conference, it seems most appropriate to emphasize 
the exposure atmosphere. 

It is necessary to control the environmental variables in an 
exposure atmosphere for two basic reasons. One reason is to protect 
the subjects from accidental exposures and overexposures. The other 
reason for controlling environmental variables is to protect the 
integrity of the experiment. If, because of faulty instrumentation 
or sloppy work, the subject is exposed to the wrong level of contami¬ 
nant, the integrity of the experiment becomes questionable. Extra¬ 
neous materials in the exposure atmosphere can also affect an experi¬ 
ment's results. 

The integrity of the exposure level must be assured in order to 
interpret the experimental data accurately. For example, slug 
exposures may elicit different responses than steady exposures, and 
although we generally design experiments to have a constant level of 
exposure, we do not always achieve it. In some of the older studies, 
which were performed without the aid of modern instrumentation. 


113 


investigators had variable exposure levels during the course of 
an exposure. Sometimes the reports simply indicated the average 
concentration, without any indication of how much the exposure 
level varied. 

DESIGNING A FAIL-SAFE EXPOSURE SYSTEM 

There are some basic principles of control which are used in 
designing a fail-safe exposure system. Control valves can be 
either normally open or normally closed, and must be energized to 
turn them to their alternate position. Such controllers will 
revert to their normally open or closed mode when the power fails. 
Clearly, in designing a test system involving human exposures, the 
investigator would want to make sure that whenever there is a 
possibility of equipment failure, the exposure would be reduced or 
stopped, or at least maintained at a near constant level. The 
investigator cannot have a system where the supply valve of a gas 
bottle is left open at the same time that the ventilation or 
dilution air closes down because of a fan failure. This could 
lead to the subjects being over-exposed to the test substance, 
with possible serious consequences. In addition, the integrity of 
a whole series of experiments could be ruined. 

Another principle or variable that has to be considered in 
experimental design is the temporal response of the test system. 
How rapidly can the exposure concentration be raised or lowered to 
achieve the appropriate level of exposure? If the concentration 
starts to go up or down for reasons extraneous to the experiment, 
how rapidly can the investigator bring it back? How quickly can he 
take action, either manually or automatically, that will keep the 
concentration within prescribed tolerance limits? These are the 
basic elements of feedback response that have to be considered in 
the experimental design, and these variables are part of the 
specifications investigators have to establish in the fabrication 
or construction and installation of test equipment. 

A selection must be made between manual and automatic control 
of the test environment. How much automatic control is necessary 
or desirable, and how much interaction should there be between the 
analog output of concentrations and the individual operator or 
mechanical controller who is doing the fine-tuning of the concen¬ 
tration? Clearly, for most investigators, the answer to this 
question depends not only on what method is ideal, but also on 
what method is compatible with the budget. The absence of sophis¬ 
ticated automatic controls and data processors need not limit 
experimentation. With adequate means of manual control, many 
kinds of experiments can be performed quite successfully. 


114 


Redundancy is important in the generation, monitoring, and 
control of the test atmosphere. We do not want an experiment 
interrupted or endangered by the failure of one component of a 
system. It is relatively inexpensive to provide alternate means of 
at least monitoring and controlling the concentration. This way, if 
one element fails, the investigator can finish the day's experiment 
on the back~up system and not have to worry about losing control of 
the experiment or terminating it prematurely. 


Finally, the investigator must be somewhat compulsive about all 
the problems that could occur in the experiment, and have contingency 
pl^ris to follow in the case of an emergency, in order to protect the 
subjects and the integrity of the experiment. 

FORMATION OF THE EXPOSURE ATMOSPHERE 

The first consideration in a discussion of test atmospheres is 
methods of atmosphere generation. This discussion will be restricted 
to areas relevant to human studies, primarily concentrating on the 
ambient pollutant gases and aerosols of both oxidizing and reducing 
atmospheres. Current studies involve chambers and exposure equipment 
for studies with sulfur dioxide (SOj ), nitrogen dioxide (NO^ ), ozone 
(O3 ), carbon monoxide (CO), and sulfur oxide (SO^) particulates. 

GENERATION OF GASEOUS ATMOSPHERES 

Carbon monoxide, sulfur dioxide, and nitrogen dioxide are 
readily available as bottled gases, and we do not have to worry 
about extraneous contaminants being introduced in the process of 
generating the gas. On the other hand, for gases formed in chemical 
conversions, other products might be introduced during the reaction 
process. There are well-established systems for metering compressed 
gases into a dilution airstream to serve as the exposure atmosphere. 
Both SC^ and NOj are highly corrosive vapors, and should only be 
passed through chemically resistant lines. For NOj , which condenses 
to a liquid at room temperatures, the lines must be heated. 

Ozone, which is a very reactive and unstable gas, cannot be 
bottled. The conventional system for generating ozone uses an 
ultra-violet light source to form ozone from atmospheric oxygen. 

Aerosols, of course, cover a broad range of chemical composition. 
An aerosol is a suspension of particles in air. These particles can 
be either liquid or solid, and they come in all different particle 
sizes. One specific aerosol used in several current human studies 
is sulfuric acid. Other human studies have used other SO,^ aerosols; 
in particular, ammonium sulfate and ammonium bisulfate. 


115 


AEROSOL GENERATION 


All of the SO aerosols are soluble in water. The general 
technique for generating such aerosols into human exposure environ¬ 
ments is to use a nebulizer, which shears a liquid into a stream of 
fine droplets of the appropriate size. The size of the droplets is 
somewhat controllable, depending on the design of the nebulizer, and 
whether it is driven by compressed air or an ultrasonic transducer. 

The particle size is also affected by the concentration of the 
chemical in the water being nebulized. 

The nebulizer can generate a limited range of droplet sizes, 
and since the equilibrium size depends on the humidity of the air, 
the generators produce both water vapor and droplets, which are more 
concentrated in terms of the solute than the liquid being nebulized. 

Using conventional nebulizers, the investigator can readily 
generate particles whose predominant size ranges from 0.1 to 1 micron. 
This is usually an appropriate size in air pollution studies, because 
a large part of the SO„ aerosol in the atmosphere falls into this 
size range. 

A single particle size is not generated by any conventional 
nebulizer. The investigator generates a particle size dispersion, a 
so-called hetero-dispersed or poly-dispersed aerosol. This is not 
necessarily a bad technique, in that it produces an integral exposure 
that corresponds to the exposure people are exposed to in the 
environment. On the other hand, in calibrating our systems for 
their response and the response of our monitors for particles, 
response is usually very much dependent on particle size. 

MONO-DISPERSED AEROSOLS 

Sometimes mono-dispersed (particles of the same size) laboratory 
aerosols are needed. There is no uniform method of generating a 
mono-dispersed calibration or test aerosol over the entire range of 
particle sizes. The particle sizes that we are concerned with run 
from about a few hundredths of a micron to ten microns. 

The vibrating orifice generator (Figure 1 ) is one method of mono- 
dispersed aerosol generation in general use recently for particles 
of about one micron and larger. A pressurized liquid stream is 
forced through a small hole, which is either three, five, or ten 
microns in diamteter, depending on the desired size range of the 
droplets. An aerosol will form when the liquid stream is forced 
through the hole under pressure. However, such aerosols will be 
relatively large and hetero-dispersed. If this technique is combined 
with a high frequency electrical disturbance, which translates into 


116 


AEPOSOL 


Schematic 
of particle 
formation. 

o 

o 

0 

o 

JL 



Figure 1 . Schematic diagram of vibrating orifice aerosol generator. 
Source; TSI, Inc., literature. 


a mechanical disturbance, the investigator can make the jet break 
up into uniform droplets. With an appropriate frequency applied to 
the piezo-electric transducer, the droplet size will be about 
three. 


With the vibrating orifice, the investigator can produce 
droplets with a geometric standard deviation as low as 1.02, or 
just as mono-dispersed as possible in a laboratory, and comparable 
to the dispersion nature achieves with various pollens. Residual 
solid particles of a much smaller size can be obtained by using 
dilute liquids. This method is preferred for forming particles 
larger than one micron. 

A system cannot be run reliably with an orifice smaller than 
about two or three microns in diameter. So, the investigator is 
limited to droplets of six to eight microns and to solid particles 
of about half a micron at the smallest. 


117 


















































For the larger size particles/ there is an alternate to the 
vibrating orifice technique, the spinning disc, which produces 
aerosols of essentially the same size range and concentration as 
the vibrating orifice. 

A different technique can be used to produce a narrow range of 
particle sizes in the very small size range. As shown in Figure 2, 
mobility classifier introduces the aerosol with unit electrical 
charges at an outer annulus of a cylinder, and the particles 
migrate toward the central electrode, propelled by their electrical 
charge. There is a clean air sheath that all the particles have 
to traverse. This is important because it means that all particles 
have essentially the same radial distance to cross the central 
electrode. If the particles of the same mobility came in across 
the whole cross section, those that started nearer to the electrode 
would reach it first. 

In a poly-dispersed aerosol, where all the particles have one 
charge, their migration against the aerodynamic drag of the airstream 
toward the central electrode is determined by their size. If, at 
this point, there is a place to withdraw the aerosol on the electrode. 




Figure 2. Schematic diagrams of electric mobility analyzer tube as 
used in mobility size analyzer (left) and as particle 
separator (right). Source: Fine Particles (Liu, B.Y.H., 
ed.). Academic Press, 1976, p. 599. 


118 






























only particles of a very limited range of electrical mobility and 
particle size will be directed there. The aerosol drawn through 
the open path will have a narrow range of particle sizes. One can 
vary the particle size range drawn out at that point by varying the 
air flow velocity or the voltage differential. This, in effect, 
enables the investigator to go from a few hundredths of a micron up 
to about half a micron in mono-dispersed aerosol generation. 

This technique is inefficient in that only a fraction of the 
generated poly-dispersed aerosol is used. However, if the investi¬ 
gator is using a dye or some relatively inexpensive material as a 
calibration aerosol, this disadvantage presents no great problem. 

This technique cannot be used for larger particles because at 
above about half a micron, the particles tend to have more than 
one charge and can no longer be sorted according to their mobility. 

MONITORING THE EXPOSURE ENVIRONMENT 

There are various approaches to monitoring the exposure atmo¬ 
sphere and characterizing the concentrations of the chemicals to 
which subjects are exposed. The traditional and simplest monitoring 
technique is manual sampling, where the investigator draws a known 
volume of air at a known flow rate through a collector. For 
particles, the collector can be a filter; for soluble gases, it 
can be a bubbler; for organics, it can be a charcoal trap. The 
appropriate collector is used to trap particles with known, and 
presumably, high efficiency. 

For gases and vapors, the collection efficiency needs to be 
known and constant. If it is less than 100 percent, the amount 
collected can be corrected to compensate for the lack of total 
collection. For aerosols, on the other hand, there must be 100 
percent collection efficiency, since the collection efficiency is 
particle size-dependent, and the investigator wants to know the 
total amount, and not some estimate that varies with its particle 
size distribution. In practice, this requirement doesn't cause 
any great problem, since filters and other types of collectors 
with essentially quantitative collection capabilities are readily 
available. 

One advantage of sample collection and subsequent analysis is 
that there is almost no limit in the choice of sample processing 
that can be done, or in the range of sophisticated and sensitive 
laboratory instruments that can be brought to bear on analytical 
problems. The investigator can get the ultimate in sensitivity 
and specificity, with correction for interferences. On the other 
hand, there is a basic limitation in this procedure in that there 


119 


is a significant time lag between sample collection and the determi¬ 
nation of what was collected. Manual sampling techniques may, 
therefore, be used to back up continuous monitors, and perhaps, as 
the final arbiter on a substance's exact concentration. However, 
in themselves, they are not of much use in maintaining an atmosphere 
at a desired level. 

INTERMITTENT/CONTINUOUS INSTRUMENTATION 

Generally, therefore, investigators use two basic types of 
automated instrumentation. One is the intermittent type of operation, 
and the other is continuous. For monitoring particles, a combination 
of techniques is generally used because there is a very large 
particle range to be covered, and there is no universal instrument 
that can indicate the concentration of each particle size interval 
over the entire size range. 

One of the instruments used to measure very small particles 
(0.08 urn to 0.5 ym) is a close relative of the mono-dispersed small 
particle generator. As shown in Figure 2, the electrical aerosol 
analyzer works on the same principle of sorting out the particles 
of a poly-dispersed aerosol according to their electrical mobility. 
Instead of withdrawing the particles at a specific location on the 
axial electrode, they are collected on a current collecting filter 
at the end of the tube, and the amount of charge they deposit on 
that filter is measured incrementally. The voltage gradient and/or 
the flow rate is changed sequentially to allow a different size cut 
to reach the filter. In this way, there is a progression of size 
increments. This technique gives the investigator an accurate size 
distribution in a stable atmosphere, and, of course, attempts are 
made to keep the chamber atmospheres stable. On the other hand, it 
takes a finite amount of time to run through these increments and 
collect the size band data to get the size analysis. This tech¬ 
nique is an example of an intermittent operation. 

In many cases, this technique is unsatisfactory, especially if 
the investigator wants very tight control of the substance's concen¬ 
tration, and needs a technique that senses the particles in a 
dynamic system and continuously indicates precisely what the level 
is. Investigators working with carbon monoxide can use an infrared 
analytical technique, which does not collect the sample at all. As 
shown in Figure 3, it simply directs the gas through the sample 
tube, through which also passes infrared radiation at wavelengths 
that are sensitively absorbed by carbon monoxide. There will be an 
attenuation of that infrared wavelength because of the absorption 
of the carbon monoxide in the sample tube, and, thus, the energy 
received on the detector will vary with the substance concentration. 
Operationally, this technique is best implemented by using a 
reference tube of clean air, and getting the difference in attenua¬ 
tion between clean air and the air containing the carbon monoxide. 


120 



ELECTRONICS 


Figure 3. Schematic diagram of infra-red gas analyzer. Source: 

Air Sampling Instruments (5th edition). ACGIH, Cincinati, 
Ohio, 1978. 


Other gaseous constituents absorb infrared energy; for example, 
water vapor. However, these gases and vapors are wavelength-specific, 
so by tuning to the wavelength at which carbon monoxide has prefer¬ 
ential absorptive capacity, the effect of interference can be 
removed, giving a sensitive, accurate, and specific analysis of 
carbon monoxide. The only time lag is the insignificant amount of 
time it takes to flush the sample through the tube. This, then, is 
a commonly used method of monitoring carbon monoxide on a continuous 
basis. The sensitivity is a function of the length of the sample 
tube, which can be 10 or 20 meters with folded tubes. 

There is practically no limit in the laboratory situation to 
the sensitivity that can be achieved using this type of instrumenta¬ 
tion. Similar instruments can also be used in measuring other 
gases by choosing appropriate wavelengths of absorption free of 
significant interferences. 


121 










































An alternate method of testing carbon monoxide is an intermit¬ 
tent technique, which involves a combination of gas chromatography 
and flame ionization detection. The flame ionization detector is 
nonspecific, but by coupling it with the holdup time in the chroma¬ 
tographic column, specific analyses can be obtained because the 
investigator knows when the carbon monoxide will come through the 
column and move into the flame ionization detector. 

The flame photometric detector illustrated in Figure 4 is 
commonly used in measuring the concentrations of sulfur-containing 
gases. If a sulfur-bearing material is passed through a hydrogen 
burner, a light photon emission will result that can be detected 
with sensitive photomultipliers. It is a nonspecific technique in 
that it gives the investigator roughly an equivalent response for 
hydrogen sulfide, sulfur dioxide and some of the mercaptans. So, 
if the investigator knows that the only sulfur gas present is 
sulfur dioxide, then the test is quite specific, but if there are 
other sulfur gases, the test is not specific. In this instance, 
the investigator can attach the sulfur gas detector to a chromato¬ 
graphic column that will separate out the sulfur species so as to 
make the test specific. In laboratory situations, the procedure is 
usually unnecessary. 



Figure 4. Schematic diagram of flame photometric analyzer for sulfur 
gases, with permeation tube calibrator. Source: Air 
Sampling Instruments (5th edition). 


122 















































































In most situations, it is desirable to have a built-in calibra¬ 
tion device on the concentration monitor to ensure that the concen¬ 
tration indicated on the output chart or on the dial is correct. 

One of the more common devices used for in-line, continuous calibra¬ 
tion is the permeation tube. For the flame-photometric detector, 
the calibration device shown in Figure 4 contains liquid sulfur 
dioxide sealed into a Teflon tube. The tube is slightly porous to 
the saturated sulfur dioxide vapor above the liquid in the tube. 

The rate of permeation of sulfur dioxide vapor out of the tube is 
very much dependent on the temperature, but is constant at a given 
temperature. If the investigator holds the permeation tube within 
a constant temperature bath, he can obtain a known emission rate. 

If he gets an accurately calibrated dilution air flow, he can 
determine the concentration of the calibration gas and direct it 
periodically into the analyzer to get a span signal for the instru¬ 
ment. This is a very convenient way of calibrating. There are 
similar calibration tubes available for nitrogen dioxide, and a 
number of hydrocarbons that are readily condensed into liquids at 
approximately room temperature. 

Instruments that measure the light emitted during gas phase 
reactions of nitric oxide and ozone are used in monitoring concen¬ 
trations in chamber and ambient atmospheres. If an excess of ozone 
is mixed with the sample containing nitric oxide, as in Figure 5, 

the amount of light is proportionate to the amount of nitric oxide. 

SAMPLE 



OUTPUT 

Figure 5. Schematic diagram of chemiluminescense NO/NO^ analyzer. 
Source: Scott Research Labs literature. 


123 
















































This technique can be used for measuring nitrogen dioxide by passing 
the sampled air through a chemical converter that converts the 
nitric dioxide to nitric oxide, which can then be measured on a 
mole for mole basis. The investigator can differentiate between 
nitric oxide and nitrogen dioxide by sequential readings with and 
without the converter in-line. 

The same basic type of instrument can be used as an ozone 
monitor by feeding an excess of nitric oxide into the reaction 
chamber. Other ozone monitors are based on other chemiluminescent 
reactions of ozone, specifically, with ethylene and organic dyes. 

I indicated before that the mobility analyzer could be used as 
a particle size analyzer for small particles, but that even using 
this technique, we could not measure particles larger than approxi¬ 
mately a half micron in diameter. Fortunately, there are other 
techniques suitable for measuring the larger particles. 

The property of light scatter is used in measuring the concen¬ 
trations and size distributions of particles of three-tenths micron 
diameter and larger. When light is focused on a particle in the 
instrument illustrated in Figure 6, some of that light will be 
scattered. The amount of light that a given particle will scatter 
depends on its size. A photomultiplier can be used to detect the 
light output from each particle. The pulses can be accumulated 
according to size intervals in a multichannel pulse-height analyzer, 
and these intervals can be calibrated according to particle size. 
However, this technique is not as simple as it sounds. There are 
other properties of the particle besides its size that affect the 
amount of light scattered, including the refractive index, the 
color, the shape, and so forth, and reliable data depend on accurate 
calibrations of the instruments used. 



Figure 6. Schematic diagram of single particle optical particle 
size analyzer. Source: Climet, Inc., literature. 


124 













Investigators in the laboratory working with droplet aerosols 
or aerosols of fairly regular shape, have fewer problems than 
investigators working with particles in the ambient air, which come 
in a great variety of compositions and shapes. Thus, in the 
controlled laboratory experiment, a reliable calibration can gener¬ 
ally be developed relating the optical-inferred diameter to the 
real diameter. These instruments are not continuous monitors 
because they accumulate and sort the pulses for a given interval, 
and then display a distribution. However, the response time can be 
fairly rapid. 

MEASURING THE PARTICLE'S MASS CONCENTRATION 

Both of the methods described for measuring particle concentra¬ 
tions and size distributions, i.e., the small particle mobility 
analyzer and the larger particle light-scatter analyzer, measure 
the diameters of particles and sort them by so many numbers of 
particles in each size interval. Number concentration is important 
in many studies, but in studying toxicology and its effects on 
people or animals, the investigator generally needs to know the 
aerosol's mass concentration. Since the mass of a particle varies 
with the cube of the diameter and with the density, the investigator 
needs to know more than number distribution. On the other hand, 
the automatic machines accumulate a very good statistical base. 

The investigator comes up with fairly good approximations by using 
transformations to volume distributions. If the particles' density 
is determined, the investigator can calculate a mass median diameter 
distribution or a concentration. 

While such data transformations may be justifiable in some 
cases, the investigator is not really measuring the property that 
is being reported. It is, therefore, sometimes necessary to directly 
determine the aerodynamic size distribution, since this is the 
distribution of sizes that affects deposition in the respiratory 
tract. If a system of somewhat rediindant measurements can be 
justified, it is best to use a variety of complementary aerosol 
measurements involving light scatter, mobility, and aerodynamic 
properties. 

The beta attenuation technique combined with a two-stage 
collection system, as illustrated in Figure 7, sorts the particles 
by their aerodynamic size and measures the mass in each fraction. 

Using this technique, the air enters an impaction jet at the top, 
and particles above a cutoff size, depending on their aerodynamic 
properties, will be collected on the back-up filter. The invest! 
gator can continuously monitor the mass of accumulated particles 
collected at each stage using the beta attenuation technique. A 
carbon 14 source is used as a beta emitter. The amount of 0-radiation 


125 


TWOMASS 



Figure 7. Schematic diagram of TWOMASS mass concentration analyzer 
Source: Fine Particles, p. 551. 


that reaches the detector depends on the g-absorption in the accumu 
lated sample between the source and the detector. 

There is only about a 10 percent variation in beta attenuation 
with mass number (Z), with the exception of hydrogen, and hydrogen 
does not usually contribute much to aerosol mass. So, by and 
large, the amount of beta attenuation by the impacted particles on 
the first stage tells the investigator how much mass of material 
has been collected in large particles above the impactor cutoff 
size, and the attenuation of the particles on the second stage 
indicates the mass of small particles below the cutoff size. How¬ 
ever, the response time of this technique is not very rapid, and 
may not be adequate for feedback control of generation rates in 
chamber atmospheres. 

Another type of direct monitor of aerosol mass concentration 
utilizes quartz-crystal oscillators as mass balances, and is illus¬ 
trated in Figure 8. Very small sample masses can be detected as 
they accumulate on the quartz crystal oscillator. The quartz 
crystal is cut into a particular mode, and electrodes are attached 


126 







































Mass Sensitivity 
Distribution 



Figure 8. Schematic diagram of quartz-crystal oscillator used as 
a mass balance, showing sensitivity over crystal face. 
Source: Fine Particles, p. 489. 

on each side. When a high frequency signal is applied, the crystal 
oscillates, and its oscillation frequency depends on the mass of 
the crystal. 

When particles are deposited on the crystal, its mass increases 
and the oscillation frequency decreases, therefore, the sample 
accumulation can be measured by the change in the frequency of the 
oscillator. In modern instrumentation, frequency counting is 
relatively simple and precise, and very sensitive. Thus, infinites¬ 
imal masses produce readily measurable signals. 

However, this technique has its limitations. The sensitive 
zone does not have a uniform sensitivity. It is greatest at the 
center of the electrodes and falls off toward the periphery. 

However, it does provide a sensitive indication of mass, and with 
enough calibration to be sure of its performance under the given 
operating conditions, can be used as a sensitive mass monitor. 

Another instrument that can be used to provide an approxima¬ 
tion of mass concentration of particles in the one-tenth to one 
micron range is the integrating nephelcwtieter, which is illustrated 
in Figure 9. This technique measures the total scatter of an 


127 
















AEROSOL OPTICAL PARAMETERS 


TTJNOSTEtJ rIT,AMFMT 
LIGHT SOURCE 

CLEAN ATP AFROSOI. 



TUNGSTEN FILAMENT 
LIGHT SOURCE 

AEROSOL 



Figure 9. Schematic diagram of integrating nephelometer. Source: 
Fine Particles, p. 521. 


aerosol. The instrument discussed earlier measures the scatter 
from individual particles. The nephelometer, by contrast, measures 
the scatter of a cloud, i.e., the total scatter of all of the 
particles in the sensing zone. 

If the investigator has the proper calibration and particles 
in the one-tenth to one micron range, he can obtain a correspondence 
between the total light scatter, the b-scat function, and the mass 
concentration. This gives the investigator a rapid response, and 
is a good indicator that nothing very drastic is happening to the 
atmosphere. This test may be a good monitor of the constancy of 
the atmosphere, even if it doesn't determine exactly what the 
concentration is. 


128 






























































RECOMMENDED BIBLIOGRAPHY 


!• Drew, R.T., and Lippmann, M.: Calibration of air sampling 
instruments. ^ Air Sampling Instruments (5th Edition). 

Section I, pp. 1-1-38. American Conference of Governmental 
Industrial Hygienists, P.O. Box 1937, Cincinnati, Ohio 45201 
(1978). 

2. Raabe, O.G.: The generation of aerosols of fine particles. 

In Fine Particles (Liu, B.Y.H., ed.). New York, Academic 
Press, 1976, pp. 57-110. 

3. Grassel, E.E.: Aerosol generation for industrial research and 
product testing. ^ Fine Particles (Liu, B.Y.H., ed.). New York, 
Academic Press, 1976, pp. 145-172. 

4. Corn, M., and Esmen, N.A.: Aerosol generation. ^ Handbook on 
Aerosols. (Chapter 2, pp. 9-39.) TID-26608, NTIS, U.S. Depart¬ 
ment of Commerce, Springfield, Va., 22161, 1976. $6.00. 

5. Kerker, M.: Laboratory generation of aerosols. Advances in 
Colloid and Interface Science 5:105-172, 1975. 

6 . Drew, R.T., and Laskin, S.: Environmental inhalation chambers. 

In Methods of Animal Experimentation (Vol. IV). New York, 
Academic Press, Chapter 1, pp. 1-41. 


129 







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Discussion Summary 


Participants asked Dr. Lippman two questions: 1) had he attempt¬ 
ed to manipulate the orifice shape and jet stream pressure as a 
means of controlling particle size; and 2) had he considered 
combining the electrical charge aerosol generator with a fluidic 
vortex amplifier as a means of controlling power, speed, and size 
in the aerosol particles. 

Dr. Lippman responded that he had no personal experience with 
either the vibrating orifice or the electrical charge analyzer. 
Participants agreed that the lack of uniformity of shape and 
diameter of fibers and other particulates present a real problem 
as far as monitoring and calibration are concerned. 


131 


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Electrical Surveillance and Integrity 


G. Guy Knickerbocker, Ph.D. 
Emergency Care Research Institute 
Plymouth Meeting, Pennsylvania 


INTRODUCTION 

It is my pleasure to be able to discuss with you some of 
the many factors that contribute to the safe and effective use 
of electrically operated devices in human studies. In my 
discussion, I will draw largely on the experience of the Emergency 
Care Research Institute, which evaluates and tests devices and 
systems used for patient care. The Institute's testing spans 
both the field of diagnostic and therapeutic devices, a somewhat 
broader range than average. In general, I would judge that 
your interests would most clearly coincide with the diagnostic 
field in clinical medicine because as I perceive your work, you 
are recording physiologic variables primarily to assess the 
effect of stimuli acting on the subject. 

While electrical safety in hospitals is related to two 
different aspects of the electrical shock phenomenon, commonly 
referred to as macroshock and microshock, it is my understanding 
that for the most part your concern would center on macroshock. 
Macroshock generally refers to electrical currents that occur 
through contact points on the surface of the body. Microshock 
occurs when currents penetrate the skin barrier through conductors 
and go to organs within the body. In general, microshock 
currents concern us less than macroshock currents. 


133 


RISKS ATTENDANT TO THE USE OF ELECTRICAL DEVICES 


This presentation will concentrate on electrical risks such 
as electrical shock, inadvertent or unwanted stimulation of excitable 
tissues, and electrocution. However, there are other risks that 
must not be overlooked, and any program that intends to ensure 
safe and effective use of instrumentation and systems must consider 
these risks. Additional risks in using electrical devices include 
the possibility of fire, especially in oxygen-enriched environments; 
burns; the subtle effects of chronic exposure to otherwise subthresh¬ 
old electrical currents; or electrical and/or magnetic fields and 
mechanical trauma that may be associated with improperly designed 
electrodes or cabinets that have sharp edges. 

The risk of burns must be broadened to include burns that 
occur because of the passage of electrical current through resistant 
tissue, causing heat to be produced by joule heating, and those 
burns that occur because of chemical reactions at the surface of 
the body, caused by the passage of current through the tissue 
electrode interface. Current-induced thermal burns are not at all 
unlikely in those cases where the electrical current used is at a 
frequency above that which evokes sensation, and current densities 
can easily be so great as to cause severe tissue damage without 
any electrical shock effect. For example, the problem of current- 
induced thermal burns has been particularly acute in the use of 
the electrosurgical unit. This unit employs currents of the order 
of 1 mHz and levels that approach or exceed 1 amp. 

The subtle effects of chronic exposure to subthreshold currents 
and fields have been studied, producing much controversial data. 

It is not an area that I would judge as significant to your studies, 
but I feel you should be aware of the possible risks of chronic 
exposure to subthreshold currents and fields. 

The device that performs improperly and gives wrong information 
is a risk factor that normally is not considered. The device may 
be out of calibration, have an altered frequency response, or have 
developed an inappropriate nonlinearity. The use of such a device 
is considered a risk to the patient because it may lead to a wrong 
conclusion concerning the subject's condition. In clinical medicine, 
a missed diagnosis because of incorrect performance of a device is 
a risk whose consequences may be every bit as great as those of 
electrical shock, burn, or fire. 

THE EFFECTS OF ELECTRICAL SHOCK 

The host of effects that electrical current can cause cover the 
whole gamut of severity. For example, a subject may experience little 


134 


or no sensation upon exposure to an electrical current. On the 
other hand, electrical current may cause a subject to lose 
consciousness, to suffer severe tissue burns, or to die. Shock 
sensation can be mild as a gentle tingling at the point of 
contact; or, the subject may experience a much more general 
shock, producing a tetany of muscles that would make it impossible 
for the person to break contact with the energized circuit, 
thus holding the respiratory muscles in a contracted or immovable 
state so that breathing becomes impossible. The more general 
shock may also cause such severe muscle contractions that bones 
may be broken. Electrical current can cause fibrillation of 
the heart or other irregularities of cardiac rhythm, burns of 
the skin and deeper tissue, or set off a convulsion. 

The outcome of an electrical shock is dependent on a 
number of factors. As Table 1 indicates, an important factor 
is the intensity of the shock, usually expressed in terms of 
the current (for example, in milliamperes or amperes). 


Table 1 


Effects 

Electrical Current 

Threshold of sensation 
of electrical shock 

1 milliampere 

Failure to let go 

10 milliamperes 

Interruption of respiration 

20 milliamperes 

Ventricular fibrillation 

60 milliamperes 
to 4 amperes 

Defibrillation of the heart 

4 amperes to 10 amperes 

Prolonged respiratory paralysis 
and severe burns 

above 10 amperes 


The values in Table 1 should not be taken as clearly defined 
thresholds for these phenomena, but rather as approximate 
orders of magnitude at which these responses will occur. There 
are many other factors that affect the subject's response to a 
given current. 


135 





Ventricular fibrillation is a state of chaotic disorganized 
contraction of the heart muscle fibers that causes the blood to 
stop circulating. In human beings, ventricular fibrillation 
rarely spontaneously reverses itself, and is usually fatal 
unless treated promptly. It may seem paradoxical that an 
electrical current greater than that which causes fibrillation 
can be less lethal, but in fact, this is the case in the current 
ranges that are identified with defibrillation of the heart. 

This fact is exploited in devices called cardiac defibrillators, 
which are used to reinstitute cardiac activity. 

Duration of the shock is almost equally as important as 
shock intensity because it governs the amount of energy imparted 
to the body. Moreover, many excitatory phenomena provoked by 
electrical currents have an inverse relationship between the 
intensity of the current and the duration of the current necessary 
to evoke a response. For example, a short shock may cause a 
muscle or a nerve to respond only if the current is significantly 
higher than that current which will excite the nerve at a 
longer duration. The contact area also plays a role in that it 
frequently determines the magnitude of current that will result 
upon contact. In general, a large area of contact implies a 
lower resistance for the shock circuit, and therefore, generally, 
a greater current. 

The pathway of the shock through the body cannot be overlooked. 
A current pathway that does not include the heart, for example, 
a pathway from one leg to the other, is much less likely to 
result in cardiac irregularities than a current pathway that 
travels from one hand to one foot, traversing the torso and 
going directly through the heart. 

Frequency or waveshape of the electrical source has a 
marked bearing on how a shock affects the subject. In general, 
the body is less sensitive to high frequency electrical currents 
than it is to low frequency currents. Studies on the sensitivity 
of the heart to varying electrical frequencies show that the 
frequency at which the lowest electrical current will cause 
ventricular fibrillation is at approximately 60 Hz. This 
frequency has been chosen for electrical power distribution, 
and thus is widely available. 

The temporal relationship of the shock to periodic phenomena 
in the body sometimes will determine whether a detrimental 
effect will result. For example, very short electrical currents, 
those of the order of a 10th of a second or less, must occur at 
a specific portion of the cardiac cycle, frequently referred to 
as the vulnerable period, if they are to cause ventricular 


136 


fibrillation. Undoubtedly, there are other physical or psychological 
factors that influence the outcome of electrical shock. It is 
not outside the realm of possibility that emotional or other 
factors generally relating to the physical or mental well-being 

of the subject affect whether a response to an electrical shock 
occurs. 

Thus, in many cases it is difficult to predict the precise 
outcome resulting from an electrical shock. Time does not permit 
me to go into depth in this area, but any of the effects of electri¬ 
cal shock that seem paradoxical become much more understandable if 
these complex interactions are considered in greater detail. 

METHODS OF PROTECTING SUBJECT 

A general philosophy for protecting the subject from electrical 
risks can be summed up simply: The intention of any protective 
measure is to restrict the current that can pass through the 
subject or to limit the voltage that can be applied across the 
subject. 

There are n\amberous approaches for enhancing the subject's 
safety, for example, because inadvertent current pathways so 
frequently involve the passage of electrical current to ground, 
the subject should be protected by insultation materials or 
isolated from grounded surfaces. This reduces the possibility 
that the subject will become a portion of an unintended current 
pathway to ground. 

Electrical safety is enhanced when subject-connected circuits 
for either the acquisition of physiologic information from the 
subject or for applying stimuli or monitoring currents to the 
subject are isolated from the ground. When such circuits are not 
ground referenced, the possibility of inadvertent currents to 
ground through the patient are markedly diminished. 

Proper electrical distribution systems also contribute to 
overall safety. In this country, our electrical distribution 
systems are overwhelmingly of the grounded type, that is, one of 
the power-supplying conductors at each outlet is grounded. There 
are valid reasons why these systems have been developed, though at 
first glance it may seem that greater safety would be afforded by 
a system that has no intentional ground connections. Suffice it 
to say that the choice of a grounded electrical distribution 
system is predicated upon factors that contribute to the reliability 
of the system's performance. 

Since we have to live with the grounded distribution system. 


137 


it is necessary to follow proper procedures for installation and 
maintenance. It is particularly important that receptacles be 
wired consistently so that the grounded conductor can always be 
identified. Let me comment parenthetically that the grounded 
conductor is that power conductor that is a ground potential. It 
should not be confused with the third conductor in a power cord, 
the green wire, which serves as a grounding conductor to which the 
cases and chassis of electrically-operated equipment are connected. 
The differentiation may seem subtle, but even in devices operated 
on electrical distribution systems that do not have any of the 
power conductors grounded, it is still important in improving 
safety to ground the cases and chassis through the green grounding 
conductor. When wiring polarity of receptacles is carried out 
consistently, devices can be plugged into that system with a fair 
degree of confidence that the devices will be connected in a 
manner that will ensure the least leakage current.* 

Effective grounding may be considered an extension of the 
idea that distribution systems must be properly installed. I 
draw specific attention to this as an important factor in the 
safe operation of a system. Devices that are properly grounded 
reduce the subject's risk of exposure to adverse and inadvertent 
currents. Effective grounding includes not only ensuring that 
the cases or chassis of electrically operated equipment are 
grounded, but also that other conductive materials in the region 
in which equipment is being used are sufficiently interconnected 
to one another and to ground. When these precautions are taken, 
potential differences or sources of electrical current that could 
become a risk are harmlessly shunted away from or around the 
subject. 

Good design is a keystone to building greater electrical 
safety. In particular, a design that reduces leakage current and 
minimizes the chance of failures leading to energization of the 
accessible surfaces or subject-connected leads, reduces the risk 
of shock or adverse effects. 

Great strides have been made in recent years as attention 
has focused on what was presumed to be an electrical shock problem 
in hospitals. While studies concerning leakage current were never 
adequately documented to provide convincing proof that leakage 


♦Leakage current is usually low current that normally occurs in 
the operation of electrical devices and in pathways other than 
the intended current-carrying circuits. It emanates from the 
chassis of the equipment and is conveyed harmlessly to ground by 
the grounding conductor in the power cord. 


138 



current was causing the "electrical shock" problem, the attention 
focused on this area nevertheless stimulated improvement in the 
design of medical eguipment, so that now the leakage current in 
vast numbers of medical devices has been reduced to levels that 
are considerably lower than those considered achievable in past 
years. On the average, chassis leakage current from these devices 
is less than 100 microamperes, often as low as a few tens of 
microamperes, and leakage currents from subject-connected leads 
are routinely well below the commonly accepted limit of 50 micro¬ 
amperes. These values are commonly accepted as upper limits on 
leakage current from patient-related devices. Other equipment is 
permitted a maximum leakage current of 500 microamperes. 

In addition to system and device design and implementation, 
there are various specific devices that are frequently introduced 
into the system with the aim of increasing electrical safety, for 
example, local power distribution systems that are isolated from 
any connection from ground. Such systems limit the magnitude of 
currents associated with failures in plug and receptacle combinations 
or in power cords. They provide an added feature in that they 
permit a faulty system to operate at relatively low risk without 
interruption of power until an orderly transition to alternate 
equipment can be made or until completion of repairs. Many codes 
and standards require that these isolated power systems be used in 
anesthetizing locations, since these systems are generally not 
prone to producing sparks that could ignite inflammable anesthetics. 
More recently, awareness of the significance of improving electri¬ 
cal safety for the benefit of the patient and attending personnel 
has increased. This has led some to use isolated power systems in 
special care areas in other hospitals and at other locations where 
it is felt the need for improved electrical protection may be 
necessary. 

Ground fault circuit interrupters are capable of sensing 
small current flows to ground that are outside of the intended 
pathway, while at the same time remaining insensitive to large 
magnitudes of current flowing in the intended pathway. There is 
a widespread application for this device; in fact, the ground 
fault circuit interrupter is required by electrical codes for use 
with electrical services supplying swimming pools, outside 
receptacles, and bathrooms in newly built homes. The disadvantage 
of using ground fault circuit interrupters is that on detection 
of a fault, power to the device is interrupted, and this interrup¬ 
tion may be untenable in certain circumstances. 

The detection techniques used in ground fault circuit 
interrupters have recently been extended to another class of 
devices, resulting in what is known as a ground fault monitor. 


139 


This device can be interposed in the power line to indicate, 
either visibly or audibly, when leakage current is above the 

prescribed level. Thus, the ground fault monitor is able to 
inform the user when limits have been exceeded, without interrup¬ 
ting the circuit. Other protective devices, which are much less 
commonly used, are those that monitor the continuity of grounding 
conductors, thus assuring that adequate grounding of equipment 
is present to minimize the risk of exposure to energized surfaces. 

Two additional items also contribute greatly to the safe use 
of electrical equipment. One is an effective regular program of 
inspection and preventive maintenance of equipment. This 
practice is most effective when it is directed not only towards a 
product's safety and protective features, but also when it takes 
into consideration the performance characteristics of a device or 
system. Failure of a device to perform properly may put the 
subject at risk if, for example, because of faulty equipment, the 
subject must be retested in a program in which there is some 
inherent risk in the testing procedure. Second, the user should 
be educated in the proper use of the device and be knowledgeable 
of its safety features and its risks. The importance of this 
second item in enhancing the safety and integrity of electrical 
devices cannot be overstated. 

EXAMPLES OF TYPICAL DEVICE OR SYSTEM PROBLEMS AND SOLUTIONS 

I would like to cite some problems or failures that have a 
marked impact on the safety of devices used in everyday settings, 
for example, in the home. Power cords and plugs often are 
abused. They lie across floors and are walked on. Carts and 
tables are wheeled over them. The cord is used to withdraw the 
plug from the receptacle. People trip over the cord and put a 
strain on both the equipment and the plug. Therefore, it is no 
wonder that many safety problems arise from failures in power 
cords and plugs. Problems of this nature are avoided most 
easily by a regular program of preventive maintenance in which 
the condition of line cords and plugs is inspected for cracked 
insulation, to ensure that strain reliefs have not been abused 
or are not inadequate, and to ensure that wiring at the plug is 
correct and tight. 

Users should insist that equipment be supplied with cords 
that are strong enough to withstand abuse. It is important for 
the user to know that the cord should not be used to remove the 
plug from its receptacle. Plugs should be examined to ensure 
that ground connections have not been cut off. Plugs molded 
or^to the line cord have a history of broken .grounding conductors 
within the plug assembly leading. There is widespread skepticism 


140 


in the medical community concerning the integrity of molded plugs. 
The siutation is changing as designs improve/ but the performance 
of molded plugs must be watched closely. 

A class of devices has evolved within the past five years 
known as hospital grade plugs and receptacles. These plugs and 
receptacles have been produced especially to withstand abuse, 
particularly with respect to the integrity of the grounding 
connection. In general, these devices should be used when there 
is great concern about the electrical safety of equipment. 

These plugs and receptacles are compatible with ordinary parallel- 
blade units, and are generally identified by the presence of a 
green dot conspicuously placed on the surface. 

The innocuous little device frequently referred to as a 
cheater, an adapter that enables a two-pronged receptacle to 
receive a three-pronged plug, is one of the most insidious 
culprits in seriously degrading electrical safety. Frequently, 
it is implemented with a wire pigtail that must be fastened 
securely to a grounded point. The screw that holds the coverplate 
on the receptacle is often taken as the point to which the 
cheater is to be connected, but unfortunately, the coverplate is 
not always connected to ground. The result is that frequently 
grounding is not achieved when these devices are used. The 
obvious solution is to avoid the need for these cheaters by 
installing proper receptacles that have the third contact for 
grounding. Any receptacle should be installed properly and then 
checked immediately to ensure that it has been wired properly. 

It should also be tested with one of the simple tension testers 
that are now available to ensure that there is adequate holding 
force for each of the plug's prongs. 

Extension cords are another problem, along with their 
closely related cousin, the adapter cord. When I say adapter 
cord, I am referring to those "short extension cords" that 
consist of a plug and a connector mounted on a short piece of 
wire that permits non-standard plugs to be connected with standard 
receptacles or vice versa. Extension cords and adapters introduce 
another set of contacts in the electrical pathway that is subject 
to failure, and at least doubles the probability of a problem 
occurring. 

If they are excessively long, extension cords also add 
resistance to the power circuits and grounding conductors and 
may reduce the safety and effectiveness of the device. The 
solution is to avoid or ban the use of extension cords. The use 
of extension cords could also be reduced by providing long power 
cords on electrical devices. Occasionally, adapters may be 


141 


necessary but they should be considered as electrical equipment 
and be included in any inspection program to ensure that hidden 
damage has not occurred. 

Failures that would normally not occur occasionally show up 
in devices that expose the subject or the experimenter to potentials 
on subject-connected leads. Selection of well-designed equipment 
is crucial to minimize this risk. 

It may happen that too many grounds will occur, especially 
when an effort is made to assure that everything is well-grounded. 

In this situation, redundant grounding pathways may lead to a 
complete circuit that might include equipment contacting the 
subject. If there are strong magnetic fields in the area, 
especially at power line frequency, and these magnetic fields 
course through the area contained within the loop formed by this 
closed ground pathway, currents known as "ground loop currents" 
may be induced in the ground system. These can create, at the 
very least, interference in signals being monitored and, under 
extreme conditions, they can expose the subject to potentials 
that would not otherwise have occurred. To avoid these problems, 
grounding should be carried out carefully. In general, the 
problem can be minimized if devices are singly grounded. This 
is usually accomplished through the grounding conductor in the 
power cord. Where it is possible, grounding conductors from 
individual equipment should come to the same point or to the 
same electrical branch circuit rather than going to widely 
disparate points within the area. Except in unusual circum¬ 
stances, no wire should be added to tie equipment together. 

CODE STANDARDS AND REGULATORY MECHANISMS INTENDED TO ENHANCE 
ELECTRICAL SAFETY 

There are a number of standards and codes that users can 
turn to for guidance, and which manufacturers, whose overall aim 
is to raise the safety level of equipment and systems, make use 
of in equipment design. Many of these standards and codes are 
produced by a consensus process; that is, a process that is 
intended to ensure that all parties affected by the proposed 
standard will have an opportunity to review and to contribute to 
its development. I will briefly mention several regulatory 
bodies involved in developing standards and codes. 

The Association for the Advancement of Medical Instrumentation 
(AAMI) is a group that produces a number of voluntary standards 
for a variety of devices that are applicable in medical and 
related fields. The organization has broad representation, 
including device manufacturers, clinical and biomedical engineers. 


142 


physicians, and nurses. One standard the AAMI has created that 
is probably of the greatest interest to you is the standard that 
sets safe limits for leakage currents in health care devices. 

Another well-known and widely respected agency that produces 
codes, standards, and recommendations is the National Fire 
Protection Association (NFPA). Historically, the NFPA has 
concentrated on activities intended to reduce risk from fire. 
However, the NFPA has increasingly embraced other areas, such as 
electrical safety. It is not surprising that the National 
Electrical Code, one of the NFPA's most visible byproducts, is 
an outgrowth of its objective to reduce risk from fire. The 
National Electrical Code prescribes wiring methods which, among 
other things, are intended to minimize fires caused by poorly 
designed or implemented electrical systems. 

The NFPA has numerous other standards including one presently 
under development that would propose methods for the safe use of 
electricity in health care. This document, commonly referred to 
as NFPA 76B, when adopted, will provide a guideline likely to be 
used well beyond the walls of health care institutions. Many of 
the principles on which it is based can be adequately carried 
over into human research facilities. The codes of the NFPA are 
widely adopted, although the NFPA itself is not a code-enforcing 
authority. For example, adherence to the National Electrical 
Code is not monitored by the NFPA, rather, the code is adopted 
by local enforcing authorities or by other governmental agencies 
and is applied by force of law. 

There is an intensive international effort to produce 
standards. This effort is largely the work of an organization 
called the International Electrotechnical Commission (lEC). The 
lEC has produced a vast array of standards intended to ensure 
the uniformity of products on an international level. The lEC 
is presently refining a comprehensive document for medical 
devices. 

Underwriters Laboratories (UL) is widely recognized as an 
organization that contributes to the safety of devices and 
appliances. In general, the UL does not write codes and standards 
for other groups, it formulates them for use in assessing equipment 
submitted to the UL by manufacturers who want to obtain the 
right to place the UL label on their products. Standards formulated 
by the UL are reviewed by persons representing diverse interests 
and a broad audience outside of the UL organization before they 
are applied to devices under examination. 


The UL has earned a good reputation for promoting safety in 


143 


electrical products. Up to this time/ many of the specialized 
devices used in research laboratories have not carried the UL 
label. There are several reasons for this. In the past, manufac¬ 
turers of these devices have not found it necessary in the competing 
marketplace to seek UL listings to promote their products. In 
addition/ obtaining UL listing entails a considerable expense on 
the part of the manufacturer and any significant model change 
means that the product must be resubmitted. In the future/ we 
are likely to see more devices/ particularly those used in the 
medical field/ that carry either the UL label or display evidence 
that the device has been screened by a process similar to the 
Underwriters service or has been judged to be in conformity with 
standards being developed by the Food and Drug Administration. 
Individual investigators will have greater assurance that devices 
have been built with an eye toward safety/ as well as toward 
efficacy or desired performance. 

CONCLUSIONS 

The foregoing is a brief overview of the various factors 
that are important in assessing the safety and performance of 
electrical systems. The topic is an immense one/ which cannot 
be adequately addressed in this paper. The safe use of electrically- 
operated devices is the result of a combination of a number of 
factors/ including safe design/ implementation/ and knowledgeable 
use of equipment. To the extent that these factors are considered 
in the development and use of electrical equipment/ the risks 
encountered will be minimal. 


144 


Discussion Summary 


Discussants questioned whether it is necessary to use three 
wires in grounding rather than two, since the neutral and the 
ground are joined together in the ground system. A hypothetical 
situation was constructed in response to this question, in which 
the grounding is accomplished at the service entrance point. 

Next, it was assumed that there are two devices adjacent to each 
other, each fed by separate branch circuits, and each having its 
frame grounded to its own neutral. 

One device is a high current device, with a heater element 
that draws 25 amperes. The 25 amperes of load current goes back 
to the neutral, and the resistance in the neutral results in a 
voltage difference between the chassis of that unit and the 
point where the neutral is grounded back at the transformer. 

Next, it was assumed that the other device has no load 
current. Hence, its chassis is essentially at the same potential 
as the point where the neutrals of these two systems are grounded. 
However, because of the drop in the neutral feeding of the 
device with high current, there may be a significant voltage 
difference between the enclosures of the two devices. 

A separate grounding conductor intended to provide grounding 
for the chassis is run to prevent large load currents from 
flowing into those conductors, and to obtain a near equality of 
the potentials of the chassis. Thus, there is a practical reason 
for using three wires in the wiring system rather than two. 

Participants also discussed the problem of separate power 
supplies in a single area. One particular concern voiced is the 
possibility of power from different service panels converging in 
an area where grounding points are of different potentials. 
Discussants considered the merits of equipotential grounding, a 
system designed to prevent the occurrence of just such a situation. 


145 


The concept of equipotential grounding has been a key issue 
in the development of the NFPA 76B impending standard. Basically/ 
this standard would place limits on the potential differences 
permissible within the vicinity of a patient or subject. Provisions 
in the standard also call for a certain amount of interconnectedness 
of the grounding systems that derive from separate panels/ to 
ensure that potential differences will be minimized. 

Participants said that equipotential grounding should be an 
important consideration in the design of any facility because it 
is necessary to limit the potential differences on the grounding 
system. Besides creating risks in terms of subject safety and 
device performance/ potential differences on the grounding 
system cause interference in many physiologic recordings. 


146 


EPA HUMAN STUDIES PROGRAMS 








CLEANS/CLEVER System Approach 


John H. Knelson, M.D. 

Health Effects Research Laboratory 
U.S. Environmental Protection Agency 


The concept of controlled environmental research using human 
subjects is not new. I was given the mission about eight years 
ago by a predecessor agency of the EPA, the National Air Pollution 
Control Administration, to find out the technological accomplish¬ 
ments in this field of research. 

The result of my inquiries led to the development of the 
CLEANS/CLEVER project now underway at Research Triangle Park. 
CLEANS is the acronym for Clinical Evaluation and Assessment of 
Noxious Substances; CLEVER stands for Clinical Evaluation and 
Verification of Epidemiologic Research. 

The CLEANS facility, adjacent to the medical center complex 
on the campus of the University of North Carolina, consists of two 
large exposure chambers with an adjoining computerized physiologic 
data acquisition system. Using these computer-controlled chambers, 
researchers can expose human subjects to the same conditions of 
polluted air that are present in urban and rural areas. 

The CLEVER project consists of two mobile laboratories, each 
containing equipment identical to that housed in the stationary 
CLEANS facility. The mobile units collect and evaluate clinical 
data from epidemiologic field studies. 


149 


Both CLEANS and CLEVER are capable of closely controlling 
environmental conditions such as light, temperature, humidity, and 
airflow, and both are computer equipped to measure a variety of 
human cardiovascular and pulmonary functions. The intent of these 
two types of laboratories is to link findings obtained from field 
research with findings from controlled clinical studies. 

To study the effects of airborne pollutants on human health 
and welfare in a controlled laboratory setting, we select, with 
specific criteria in mind, human research siibjects and manipulate 
these subjects and their environment in a predetermined way. We 
define the dose, the pollutant, and the exposure regimen, and then 
we decide which physiologic, metabolic, neuroendocrine, hemato¬ 
logic, and psychophysiologic end points we intend to study. Once 
these end points are defined, we study the responses of indivi¬ 
duals who reside in a manipulated environment for a set period of 
time. 


By manipulated environment, I mean one that either simulates 
urban or rural conditions, or one that is very clean in terms of 
particulate counts and gaseous concentrations. In such an environ¬ 
ment, factors such as temperature, humidity, light intensity, and 
sound levels are controlled to predetermined values. 

What kind of machinery do we use in our experiments? How do 
we get our data? How do we process our data? How do we validate 
it? How are we assured that we are doing what we think we are 
doing, both in terms of manipulating the environment and in acquir¬ 
ing the physiologic or biologic data that we think we are acquiring? 
These questions form the subject of this discussion. 

During the formative years of the CLEANS/CLEVER program, I 
visited every laboratory conducting environmental research that I 
could identify. One of the first places I visited was Dr. Kerr's 
laboratory. Dr. Kerr impressed upon me that a study design that 
depends upon external environmental conditions is subject to many 
problems. 

Some of the early experiments at Ranch Los Amigos were design¬ 
ed to study and document the physiologic functions of people 
residing in a clean environment. To gather data on polluted air, 
the researchers depended on the ambient, supposedly polluted, air 
obtained from the laboratories' urban location. Although there 
were certain merits to that experimental design, the research was 
subject to the vagaries of prevailing weather conditions. I 
decided not to contend with the kind of problems such as experi¬ 
mental design involves, and instead would design a laboratory that 
had the capability of stimulating in a highly reliable, predicta¬ 
ble, and well-characterized fashion the atmospheric conditions 
that occur in our urban environments. 


150 


A design of this type is a leap from the real world into the 
stimulated laboratory world. You pay something for that leap, but 
you gain better control of your experiment. Over the years that we 
have been developing the EPA Human Studies Program, the substantial 
advances made in air quality assessment have diminished the price we 
pay for simulating the real environment. The advantages, however, 
of being able to control our experiments have remained the same. 

Another impression I received from the laboratories I visited 
was that most investigators were able to acquire a tremendous 
amount of data, but they really did not have the logistic capabili¬ 
ty to thoroughly examine the data they acquired. It was clear 
that if the data were computerized and preprocessed, it could be 
examined as it was acquired. Moreover, preprocessed data is much 
easier to analyze than thumbing through stacks of line printer 
output in an attempt to make sense out of the data after the 
experiment is finished. The practicality of preprocessed data plus 
the advances in air quality measurement and the advances in the 
technology for simulating environmental conditions helped us 
decide to computerize and automate our environmental control 
system. 

It has become a cliche to have a complete feedback loop, in¬ 
dependent of human intervention, to control sophisticated environ¬ 
mental simulations. We thought we could gain better control of our 
studies and construct a much more sophisticated environmental 
simulation if we used high-speed computer equipment capable of 
constantly adjusting the environment for us as the feedback loop 
worked. To this end, we evolved an automated physiologic data 
acquisition system and an automated environmental control system. 

A sine qua non of clinical research is to control the research 
project so effectively that the risk to the human participant in 
an experiment becomes vanishingly small. If you depend on extensive 
mechanical support systems to provide a simulated environment, an 
interjection of many safety systems into that environmental support 
machinery provides layer after layer of redundancy for safety s 
sake. 


If you depend on manual control of your mechanical support 
system, it will probably work reasonably well, but a manual system 
does not have the reliability of a system that processes many data 
points per second. Such a system gives you real-time appreciation 
of what the analyzers are showing in controlled environmental lab¬ 
oratories. 

The program concept of human studies began in 1969 during 
the period of Earth day, the end of the Vietnamese war, and the 
general unrest on the nation's campuses. At that time, it was 


151 



difficult for a federal agency, even a benign one such as the 
National Air Pollution Control Administration, to communicate 
effectively with university administrations. However, we were 
well received at the University of North Carolina, and our reception 
by the University is essential to any success that we may ever 
attain. 

Because the CLEANS/CLEVER program would take a long time to 
get started, we decided to install a less sophisticated mechanism 
that we could use right away. We built an acrylic chamber that 
has been the source of much valuable data. In a few months we 
were able to design and successfully conduct an experiment with 
reasonably well defined sulfuric acid aerosols. The chamber has 
become a valuable pilot laboratory for debugging experiments; it 
will be moved into the bigger, more expensive facility. 

We spent roughly two years preparing design specifications 
for the research facility. The contract we awarded included 
research, development, design, and construction. Research and 
development was such a large fraction of the overall cost that we 
decided that the construction of duplicate laboratories, in terms 
of hardware costs, was not inordinately expensive. Consequently, 
two laboratories, identical as far as physiologic data acquisition 
is concerned, were installed side by side. The use of two lab¬ 
oratories doubles the throughput of the entire facility at rela¬ 
tively little additional cost. 

Physiologic Data Acquisition System (PDAS) 

Our physiologic data acquisition system provides us with a 
variety of information, much of which concerns cardiopulmonary 
functions because that is the subject we study most often. We 
receive information either directly from the subject, or from 
instruments attached to the subject. The data measured by the 
instruments, such as gas concentrations and flow rates, travels 
through analogue signal channels outside the chamber into buffers 
and multiplexers, and then into the computer system where they are 
digitized. 

Communication lines allow the computer to control certain 
aspects of an experiment without human intervention. One of the 
simpler tasks is time of use calibration of the instruments. This 
task is not quite as simple, for instance, as control of the 
treadmill during exercise stress testing. Developing software for 
exercise stress testing (i.e., exercise electrocardiography) 
proved more difficult than anticipated, so we decided to write the 
algorithms for the simpler tests (spirometry and body plethys¬ 
mography) and apply what we learned from those tests to the develop¬ 
ment of the exercise stress testing programs. 


152 



^®c:6ssary/ w© can operate the facility without the ccxnputer» 
In the event that the ccmputer is inoperable for a predictably 
short period, we can continue an expensive oxperiment by acquiring 
our data offline until the computer is functional once again. It 
^ould be inconvenient to insert offline data into the computerized 
data, but I think I would prefer to do that rather than throw away 
the whole experiment. 

Our PDAS is not totally independent of the human operator. 

The digital data base processed by the computer supplies the 
operator with information he needs to decide whether to intervene 
or to allow the system to operate independently. The software can 
prompt the operator to perform certain tests, or it can perform 
the tests automatically. During the course of an experiment, 
direct visual communication with the subject inside the laboratory 
is maintained by a closed-circuit television camera. In addition 
to an electrocardiogram attached to the subject, there is an 
oscilloscope readout of the subject's pulmonary functions. The 
readout is displayed on two CRT screens as either digitized wave¬ 
forms or as alphanumeric information. 

The use of this equipment allows for human intervention in 
our highly mechanized system. For example, when a simple spiro¬ 
metry test is conducted, within a few milliseconds after the 
forced expiratory vital capacity maneuver is completed, a digitized 
waveform shows on the CRT screen. Identifying hatch marks indicate 
where certain software decisions were made. If the operator is 
not satisfied with the point where the pattern recognition algorithm 
indicates the expiration occurred, he can capture the identifying 
mark with the cursor and move it to where he thinks expiration 
actually occiirred. When the operator moves the cursor, the ccmputer 
will create a file that has both the original digitized data and 
the derived data for the waveform as it was defined by the computer. 
Next to that file another file is created containing the new 
information calculated on the basis of where the new cursor mark 
was placed. 

The nerve center of the PDAS is what we call the functional 
keyboard — a panel of 25 numbered pushbuttons (five rows of five 
buttons). By manipulating the keyboard, we can call up a variety 
of software programs. We can choose any part of a program by 
simply pushing the right number on the keyboard. Whenever any 
test is designed that we want to include in our system, we can 
write the appropriate software for that test and insert it into 
the entire algorithm. 

When the keyboard panel is not lighted, the buttons cannot be 
pushed. When the panel light flickers, the buttons are ready to 


153 


be pushed/ at which time the panel becomes solidly backlit. The 
solid lighting indicates to the operator that he may proceed with 
whatever routine he has chosen. If the operator wants information 
on spirometry, the system does not compel him to go through the 
entire program of spirometry in a predetermined sequence. If 
desired, the operator may choose certain components of the program, 
such as forced inspiratory volume or forced vital capacity. Thus, 
the keyboard provides for human control of the PDAS; it gives us 
the option of deciding when, and to what extent, to perform a 
given test. 

Another facet of this system is the alternative to either 
throwing out or keeping data -- in other words, a way of saving 
data we suspect might be incorrect so that we can check it later. 
When we want to save data of this type, we put a special flag on 
it by hitting the "poor data" button on the keyboard. If desired, 
we can enter free text in a file that might say, for example, that 
the subject coughed halfway through his FVC and we are uncertain 
whether or not the data has been changed. 

The other portions of the software package are not yet written. 
The system is really infinitely expandable and alterable because 
it is totally software dependent. Expansion is limited only by 
our imaginations, what we decide we want to do, how much core we 
want to buy, and how many new programs we plan to write. 

Environmental Control System 


A class 100 clean room is an artificial, arbitrary engineer¬ 
ing requirement, but it is one that would warm the cockles of most 
investigators' hearts. We decided that a class 100 clean room 
would be our objective for our environmental control system. 

We can achieve, relatively easily, class 1,000 clean room 
conditions. Such conditions may not be clean enough for assembl¬ 
ing microcircuits, but they are clean compared to the clean air 
that people breathe most of the time, and class 1,000 conditions 
are a nice control for us. 

The outside air is prefiltered. To properly control tempera¬ 
ture, we must use both heating and cooling in series. To maintain 
good control of relative humidity, we dry the air and then reinject 
the desired amount of water vapor. The air comes in through the 
top of the controlled environmental laboratory, where diffusers 
provide reasonably laminar flow from ceiling to floor. The air is 
exhausted out through the perforated floor of the laboratory, 
through several banks of high-efficiency particulate filters. In 
addition, the air is filtered through activated charcoal. 


154 



We have several levels of safety control as far as our environ¬ 
mental system is concerned. The delivery of pollutant gases into 
the air flow system is through low pressure lines, so if any loss 
of integrity of that system occurs inside the building, we are not 
dealing with a high pressure system coming off the supply bottles. 

There are, at various points in the system, critical orifices 
through which you cannot push air any faster than a certain flow 
determined by the size of the orifice. This puts a mechanical ceil¬ 
ing on the level of pollutant that we can put into the laboratory. 
The actual makeup of the laboratory air is detemined by the pol¬ 
lutants injected into the air flow just proximal to the axial vane 
fan; therefore, pollutants are churned up and well distributed. 

For any particular circumstance, the volume of air flow is a 
function of the damper setting, the speed of the fan, and the pitch 
of the impeller blades on the fan. When these three factors are 
adjusted simultaneously, they will determine the air flow through 
the laboratory. 

Allow me to back up a moment to point out the difference in the 
two laboratories that I mentioned earlier. They are identical with 
respect to gaseous air pollutant capability — specifically, ozone, 
sulfur dioxide, nitric acid, nitrogen dioxide, and carbon monoxide. 
In one of the laboratories, we are installing the aerosol gener¬ 
ating and monitoring capability. The air flow for one of the 
chambers had to be a little bit different than the air flow for 
the other in order to accanmodate the aerosol capability. 

The aerosol generators can put any water soluble substance 
into the air stream. The number of particles and the size of the 
particles is determined by the concentration of the solution 
supplying the nebulizer, the solution flow through the nebulizer, 
and the air flow through the nebulizer. These three parameters 
determine the mass concentration in the chamber and the particle 
size distribution. The composition is determined by whatever is 
put into the solution. That is why, for instance, we do not bypass 
the hepa filter if we get it down to clean conditions. Then, once 
most of the unwanted particles are eliminated from the airstream, 
we bypass those filters to filter out all of the aerosol we intro¬ 
duce in the system. 

The solenoids either opened or closed, and the length of time 
spent in the open mode or in the closed mode, determines the concen¬ 
tration of pollutant gas in the chamber. These are hydraulically- 
operated, compressed air solenoid valves. 


155 


A high-limit alarm allows the operator to intevene, if neces¬ 
sary. Even before the alarm goes off, the operator can monitor the 
actual analogue output of the sensors. Because he knows the 
relationship between analogue outuput and pollutant concentration 
in the laboratory, the operator is able to find out whether or not 
the predetermined pollutant concentration is actually in that 
laboratory. 

If the computer does not maintain the predetermined concentra¬ 
tion of pollutant, the operator is able to intervene by changing 
potentiometer settings or by manually overriding the computer. In 
the case of either computer malfunction or computer crash, we 
think the operator can successfully maintain the predetermined 
concentration in the controlled environmental laboratory so that 
the experiment can continue. In the event that this is not pos¬ 
sible, we have made provisions for a single button to be pushed by 
the operator which will abort the experiment and purge the chamber. 
The button turns on the fan and opens the fusable link dampers. 
Within a few seconds the chamber is completely evacuated of that 
particular pollutant concentration. 

We are most concerned about data quality control. Health 
Effects Research Laboratory personnel are responsible for and are 
in charge of all experiments. However, because we do not have 
adequate engineering support staff in our laboratory to conduct 
these experiments, we have a rather substantial operating and 
maintenance contract with Rockwell International. We keep a close 
watch on the laboratory environments that are maintained by our 
contract personnel. Conceptually and administratively we monitor 
the data quality control for both the physiologic data acquisiton 
system and the environmental control system in the same way. 

From time to time, though, an independent audit is conducted 
by a third party and gives EPA a report. From that and from our 
observation of the operation and maintenance of the environmental 
laboratory, we will produce a data quality report from time to 
time. 


I would like to touch on some of the main aspects of the data 
quality control, and some of the philosophical points in data 
quality control. Very simply, we constantly make mechanical 
status checks. For instance, with regard to the air flows, we know 
that in order to properly maintain the environment, air flows at 
certain points must be within certain limits, and that is checked 
constantly. For temperature and humidity control, we take correct¬ 
ive action to make sure that dampers are accurately set and that 
the integrity of the circuits is sound. Finally, all the analyze¬ 
rs are frequently calibrated with MBS referable standards. 


156 


As far as the pollutant system is concerned with respect to 
data quality control, we measure gas concentrations, obviously, 
but we also look carefully at the gas flow rates past certain 
points* If they are not within certain bounds, we know that even 
though gas concentrations might be what we think they should be, 
there is something wrong with the system. Solenoid positions 
obviously have to be maintained in a certain configuration in 
order to produce the gas concentrations we want. 

Data quality control of the physiologic data acquisition 
system is somewhat more complex because it is more difficult to 
make sure the computer is giving information that closely cor¬ 
responds to the data that are actually coming from the subject. 

One of the ways to assure the reliability of computer information 
is to compare it with canned or known input. Canned input is 
synthetic data; for example, an ECG simulator is used or spiro¬ 
metry data are mechanically produced. Such data are the same day 
after day. Anytime you wish to check whether the numeric data 
flashed on the screen are the same as they were the day before, 
you can run the canned, or known, data through the computer. 

We use physical calibration just as anybody does in any 
laboratory, but we are also striving to achieve a high quality of 
electronic time of use calibration. This is accomplished by using 
the computer, which can detect any deviation in electrical signals. 
If one or five milliwatts is put through, a certain signal is 
obtained from the computer. Split signal redundancy analysis is 
yet another approach. This permits us to split a given electrical 
signal and run it through both of our computers. If the computers 
are working properly, the same answer is obtained from both of 
them. 


If we get different answers, we may not know which one is 
right, but at least we know that a problem exists. Trend analysis 
is simply the intelligent and knowledgeable human operator watch¬ 
ing the computer output for suspicious changes in the data. This 
is a very soft kind of data quality control, but the computer 
output of good trend analysis information probably will tip us off 
to something. 

Algorithm error analysis is, of course, applicable to any 
algorithm, regardless of whether the algorithm is operating a 
chamber or whether it is processing data obtained from a piece of 
physiologic equijMnent. This type of analysis provides us with 
built-in range checks. We know, for example, that vital capacity 
should not be 15 liters or 500 cc.'s. If a data bit is identified 
as unbelievable by our definition in the algorithm, then the data 
is flagged so that we can examine it. 


157 


I would like to conclude with a quick overview of where we 
might be going with this. We have completed the first 30 subjects 
of ozone adaptation in clean air, and we hope the experiment will 
reveal some answers about differences in lung performance as it 
relates to the length of time a subject has been breathing ozone. 

We are very concerned about nitrogen dioxide and other environ¬ 
mental stresses, such as heat, in conjunction with various pollutant 
stresses. By January 1978, we should have a good capability of 
generating aerosols, and by July 1978 we should actually be able to 
generate and monitor them with online computer control. 

Finally, our staff is now preparing the comprehensive program 
plan that will describe how this facility will be used for the 
remainder of this decade. We know what research capabilities we 
have and we know the priorities and needs of the Environmental 
Protection Agency. We encourage your participation is this pre¬ 
paration process. Your ideas, your thoughts, and your proposals 
are a national resource. We invite you to join us as correspond¬ 
ents or, on occasion, as visiting scientists. 


158 


SPECIAL CONSIDERATIONS AND 
APPROACHES IN ENVIRONMENTAL 
CUNICAL RESEARCH 


Moderator: Philip Bromberg, M.D. 



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Introduction to Panel Discussion 


Philip Bromberg, M.D., Moderator 
School of Medicine 
University of North Caroiina 


I should like to disregard the typical question of what is 
response and vdiat is disease* Dr* Bates^ who unfortunately is not 
here to defend himself, suggests that response is disease, and 
that the burden of proof is on those who claim that response is 
not disease* 

I should like to proceed to the question: What does one 
measure as the effects of the agents that we are examining? How 
do we measure them? When do we measure them? 

The first thing that is measured is gross toxicology, for 
example, excess mortality during air pollution academics* After 
that, the researcher looks at the causes of the symptomatic and 
mortality effects that have been produced* 

Perhaps the first approach is to look at lung function* As 
researchers probe deeper into the fianctions of the lung, they 
develop new concepts of how the lung works, and produce more and 
more elegant and sophisticated tests of lung function* These 
studies are applied to man, as well as to animals* 

Then, newer indices of lung actions are developed* When we 
look at these new indices, the way they are studied progresses 
from gross (e*g*, the effect of ozone in fairly large concentrations 
on airways is epithelium slough) to refined, to extremely elegant* 


161 


In more refined studies, the researcher can look not only at the 
gross destruction of the epithelium, but also at the rate of turn¬ 
over of epithelial cells, which is a more refined index of the 
death rate of epithelial cells. 

Finally, the researcher can begin to study even more elegant 
indicators, such as how permeable the airway epithelium is to 
materials deposited in the lumen of the airways. This permeability 
overall may be affected by the so-called mucous layer, although it 
is not clear that the mucous layer is really a continuous layer. 
Because it is an epithelium, the airway lining is characterized by 
"tight junctions" between the epithelial cells. In many tissues, 
these are known to limit the permeation of both the small and 
large molecules. 

Some evidence indicates that noxious agents, gases, can 
affect the intactness of the tight junctions of the respiratory 
epithelium and its permeability characteristics. The latter 
effects allow materials to be deposited in the airway, where they 
penetrate the deeper layers of the epithelium and act upon smooth 
muscle vasculature and mast cells. 

What exactly are we to measure and how are we to measure it? 
These are questions that are subject to continual development and 
refinement. The highlight of this kind of approach is always 
mechanisms. We are not just interested in gross effects, but also 
in the mechanisms that produce these effects. 

I think that to answer this question coherently, governmental 
regulatory agencies, such as the EPA, which is responsible for 
developing concrete air quality standards, must be concerned with 
mechanisms. Even though this conference focuses on human studies, 
we should not limit our attempts to define air pollutant levels to 
such studies. Our studies must be accompanied by an attempt to 
understand the mechanisms that produce the effects. 

Another difficult topic is the independent variable. We have 
already heard that there are many problems pertinent to the identi¬ 
fication and measurement of the independent variable. There are 
multiple agents. There is, of course, the ordinary dose effect 
relationship. There is the problem of timing--when, after exposure, 
should one look for effects? How long should exposures be? What 
about tolerance? What kinds of interactions are present between 
external noxious agents; interactions with other pharmacologic 
agents; interactions with physiologic stimuli, such as exercise; 
interactions with temperature, humidity, and particles? These 
questions give rise to so many permutations and combinations that, 
to perform really pertinent experiments, I think one must have a 
particular objective in mind--not merely a broad hypothesis. 


162 


For example/ a researcher ought to examine the mechanisms of how 
a particular noxious agent works, and consider what type of 
experiment can be devised to obtain more information about it, 
rather than attempt to answer a question such as "Is this gas 
noxious?" 

Another major problem is the subjects we use in our experiments. 
Whom should we choose as our subjects? Should our subjects be 
healthy, or should we be looking at subjects who have some type of 
disease? Disease, as well as health, is difficult to characterize 
in human beings. 

Finally, what are the effects of informed consent on human 
subjects? Does the subject's knowledge of what effects to expect 
influence his symptoms, and consequently, the test's so-called 
objective findings? Real problems can arise from this element of 
the equation. Again, I plead that researchers should think 
mechanistically rather than simply be satisfied with the observation 
of one effect or another. 

Now, the panel and the audience may or may not agree with 
everything I have said. I would like each member of the panel to 
have a chance to make a statement of his own. Then we can have 
some discussion after each member of the panel has had an 
opportunity to talk, and follow up with a general discussion. 


163 


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statement 


Robert Frank, M.D. 

Department of Environmental Health 
University of Washington 


I want to respond to some of the things Dr. Bromberg mentioned. 
My personal philosophy regarding clinical research can be stated as 
follows: First, clinical research can be directed toward under¬ 

standing phenomena (Dr. Bromberg referred to this); that is, 
toward providing a basis for an observed response. Second, clinical 
research can be applied to describing dose-response relationships 
for a particular agent. 

Both objectives are important, particularly the latter. Dose 
response relations affect standard setting, which in turn can 
significantly affect society. 

I also think the investigator engaged in the latter type of 
clinical research should be prepared to discuss the biological 
significance of his results. At the very least he should attempt 
to assign some weight to his results. If he fails to do this, 
then other scientific investigators perhaps ought to take up the 
task, because if they do not, the task will be taken up by non¬ 
scientists. 

As Dr. Bromberg indicated, it is entirely possible that the 
particular functional parameter under examination -- the so-called 
dysfunction the researcher may have observed -- may, by itself, be 
readily tolerated or quickly reversible. Alternatively, it may be 
insignificant, but have important secondary effects. Dr. Lippman 


165 


has stated, for example, that the transient bronchoconstriction 
associated with exposure to irritants may in turn lead to increased 
deposition of inhaled particles, which obviously has implications 
for biological dosage. 

But, if the investigator suspects that a dysfunction has 
significant secondary effects, then he should state his hypothesis 
and test it. At the moment, I think there are a number of so- 
called positive findings in clinical research that have received 
more attention than they deserve. 

There may be some reasons for this. No one likes to profess 
that the product of his work, the effect he has observed, has only 
questionable or minimal importance. To do so means monumental in¬ 
attention to the researcher's study and a loss of funds. 

A word about functional testing. We rely rather heavily on 
measurements of ventilatory function and respiratory mechanics. 

There is good reason for this reliance. In the past these measure¬ 
ments have been extremely useful and revealing, but we must remain 
resourceful and be prepared to move beyond them, to recognize when 
testing our hypothesis may demand additional techniques. 

For example, Lippman has shown with sulfuric acid aerosol 
administered to donkeys that in the presence of little or no 
changes in respiratory mechanics, there may be significant depres¬ 
sion of mucociliary clearance. 

I am somewhat surprised to notice that in assessing changes 
in function that are due presumably to reflect bronchoconstriction, 
many of us still depend exclusively on a ventilatory test that 
requires a maximum inspiratory maneuver. Years ago, Nadel showed 
that a maximum inspiration can abolish, at least temporarily, 
bronchoconstriction. Also years ago, Arend Bouhuys showed that a 
partial expiratory flow-volume effort, which avoids this danger of 
abolishing reflex bronchoconstriction, can be more revealing than 
a flow-volume effort begun following maximal inspiration. Perhaps 
this is a test we ought to use more often. 

Furthermore, when we start experiments involving ultra-fine 
or accumulation mode irritant aerosols, as for example sulfuric 
acid, we ought to emphasize tests that assess small airway function. 
After all, such particles are most likely to land in the periphery 
of the lung. This suggestion, at least in my own experience, is 
borne out by studies on guinea pigs exposed to submicrometric 
aerosols. Their dynamic compliance can be affected more often than 
their total flow resistance. It is not easy to assess small 
airway function. The tests are often time-consuming and their 


166 


interpretation may be open to debate. Such tests can beccxne 
distracting in studies in which the functional changes may be 
occurring rapidly. 

In my judgment, the measurement of closing volume has not 
been too revealing. Also, the forced expiratory flow rate at 25% 
of vital capacity has a rather high variance so that subtle changes 
in small airway caliber may elude detection by this means. 

Dynamic compliance, which may be useful for detecting un¬ 
evenly distributed changes in small airways or parenchyma, is 
another test that is difficult to accomplish. It requires an 
esophageal catheter and a well trained subject. It is not always 
easy to control what has to be controlled, that is end-expiratory 
lung volxame and tidal volume, when the subject breathes at dif¬ 
ferent frequencies. Perhaps we should experiment more with the 
helium oxygen techniques developed at McGill University. McFadden 
found this technique to be quite revealing in his studies of 
exercise-induced bronchoconstriction. One problem may be the time 
required to perform it. 

Presently, my belief is that we ought to focus more attention 
on what I term the "hyper-reactive subject"; in other words, a 
subject who is otherwise normal and with no known underlying chest 
disease. For the sake of discussion, I will accept Amdur's defini¬ 
tion of a hyper-reactive subject as someone whose functional 
change during exposure to a pollutant is at least three times 
greater than the average group response. Amdur reviewed the 
literature and noted that a number of investigators working in the 
field encountered one or two subjects in their group who suited 
this definition. For the moment we will exclude allergy as the 
basis for hyper-reactivity. 

Several questions might be asked about this type of subject: 

Is the hyper-reactivity typical of the subject? That is, if I 
observe an exaggerated response on Monday to a pollutant, will it 
b© present on Tuesday, Wednesday, Thursday, and one month later? 
Does it have some plausible or identifiable mechanism? For example 
is it a matter of internal dosage? 

You may recall the observations of researchers at New York 
University years ago suggesting that the pattern of particle 
deposition in the periphery of the lung is determined in great 
measure by morphometric factors. Just as the aerodynamic character 
istics of an aerosol influence its rate and site of deposition, so 
may airway and alveolar dimensions and ventilatory pattern. All 
of these biological factors can vary considerably within the 
normal population. Such variations among lungs, and particularly 
within a lung, may become very important once lung disease has 


167 


been established. There are likely to be variations in the distri¬ 
bution of ventilation within a diseased lung, leading to local 
"hot spots." Morphological factors of this type are likely to 
impose differences in dosage, among or within lungs, over long 
periods of time. 

I wonder how much differences in bronchoconstriction among 
subjects inhaling drugs such as acetylcholine or mecholyl may be 
due to differences in the deposition rate or dosage. 

An alternative explanation is that the exaggerated response 
may reflect an altered or increased responsiveness to the same 
fixed dosage. In his recent work on dogs, Nadel found that follow¬ 
ing ozone inhalation, there was a clear-cut increase in the broncho¬ 
constriction in these animals produced by parasympathomimetic 
drugs. This hyper-reactivity reached a peak about 24 hours after 
the ozone inhalation and thereafter receded. In this instance, 
neurophysiological changes in function produced by exposure to 
ozone, apparently led to hyper-reactivity. He noted, too, that 
infection may produce the same result. 

Functional or inflammatory factors of this type are likely to 
impose differences in dosage over limited periods of time. As I 
see it, if we could identify and understand the basis for hyper¬ 
reactivity, we might be able to predict who among the population 
is at greatest risk. The rewards might be especially high for 
occupational settings, wherein the workers at greatest risk might 
be identified before any impairment of health occurred. I think 
it is a worthwhile hypothesis toward which research efforts should 
be directed. 

To move to another subject, it is probably a truism that we 
ought to ccxnbine pollutant exposure with other forms of stress 
during clinical experiments. This is particularly true when we 
administer realistic concentrations of pollutants to healthy human 
subjects. The most obvious concurrent stress is exercise. Studies 
including both these variables, that is, exposure plus exercise, 
have been well exploited by Drs. Bates and Horvath. It is probably 
true that the more vigorous the exercise, the more likely the 

effect on the response to the air pollutant. Some of the reasons 

for this phenomenon are known. The increased ventilation that 
occurs during exercise causes a greater amount of the pollutant to 

be introduced into the respiratory system per unit of time, and 

the increase in instantaneous flow rates that occurs during exercise 
is associated with a reduction in the scrubbing efficiency (fraction¬ 
al uptake) of the upper airways for soluble gases and particles. 

This is particularly true when the subject switches from nose to 
mouth breathing during exercise. 


168 


In addition/ there is probably some alteration in the sites 
of transfer of these gases and particles in the lower airways. 

For example, when a subject ventilates at high flow rates while 
inhaling a particle of sulfuric acid, as during exercise, the pH 
of the particle at the instant of impaction in the airways is 
probably lower than during quiet breathing. This difference in pH 
may be the result of two phenomena. First, the particle may be 
less hydrated during exercise when there is less time for it to 
absorb water (before impaction) and therefore, less time for the 
water to dilute the hydrogenion concentration. Second, there is 
also less time for any chemical transformation or neutralization 
of the particle by ammonia in the upper airways. 

There are other forms of stress that have not been adequately 
explored. Recently, Dr. Horvath has begun combining heat with 
exposure to pollutants. We have not, to my knowledge, rigorously 
studied the effects of a combining cold and a pollutant, especial¬ 
ly when a soluble gas is combined with a droplet aerosol. Certain¬ 
ly, one of the impressive features of epidemiologic studies is 
that sudden changes in ambient temperature may overwhelm the 
effects of pollution. 

Finally, an approach that I think is potentially as rewarding 
as any other is to study the effect of psychological stress on 
response. We have not yet begun to design appropriate psycho¬ 
logical stresses for this purpose, and I have no idea how to 
proceed. It is possible that noise might be an effective co¬ 
stressor. 

My last point is really designed to evoke a not-always-friendly 
response. In clinical research, we are beginning a generation of 
experiments in which multiple pollutants are administered simultane¬ 
ously for several hours. The ostensible purpose of these experiments 
is to see if the ccxtibined effects of the simultaneously—administered 
pollutants are addictive, synergistic, or conceivably, antagonistic. 

I have misgiving about a number of these studies as follows: 
Unless there is a plausible chemical or physical basis for inter¬ 
action among the pollutants that will cause them to form some new, 
presumably more irritant species or end product, or unless there 
is a plausible argument why two or more pollutants are likely to 
affect the same biochemical or physiological function, or at least 
affect separate functions that are interdependent, the results of 
such studies are likely to be disappointing and ambiguous. 

Experiments of this type are extremely complex in design. 

They require repeated observations on the same individual to 
establish whether synergism, et cetera, has occurred. I have been 
impressed with the variance in the responses of subjects to the 


169 


same pollutant on different occasions/ as well as the variance in 
the functional parameters that have been tested. 

The researcher is likely to end up with the product of these 
several errors/ which makes it extremely difficult to detect all 
but the most dramatic effects. I could readily support an attempt 
to study the biological consequences of interactions among sulfur 
dioxide/ ozone/ and some droplet aerosol. The analytical chemist 
tells us that there is a reasonable likelihood for a heterogeneous 
reaction among these agents with the formation of an irritant 
small particle. 

But I would be less enthusiastic about mixing agents like 
sulfur dioxide/ nitrogen dioxide/ and carbon monoxide. Unless I 
am mistaken/ these three gases do not interact and their sites of 
effect are by and large different. I would seek the rationale for 
such a mix and would not be satisfied to learn that it is "because 
all three gases are found in polluted air." Our resources are too 
limited for that sort of luxury. 


170 


Discussion 


DR. HAZUCHA: Dr. Frank mentioned hyper-reactive subjects. 
Certainly, you have to find out how to identify and study these 
subjects. But from my experience with testing 20 or 30 subjects, 
we usually find one or two who do not react at all. To get a true 
picture of the response, we have to identify not only hyper-reactive 
subjects, but the hypo-reactive subjects as well. 

DR. FRANK: I couldn't agree with you more. Again, I am 
speaking as a member of a society concerned about protecting 
people. It is true that you may learn as much about this phenome¬ 
non of hyper-reactivity by pinpointing what it is about the subject 
that protects him, or dampens the result, as you do by identifying 
what it is that exaggerates the response. 

DR. CAVENDA: You have not mentioned repeated tests (other 
than the fact that the subject reacted on Monday, Tuesday, Wednesday, 
Thursday) to determine if, over a period of time, a subject might 
be tested for changes in response. For instance, a subject might 
experience anxiety the first time he engages in a new activity 
defined by the testing procedure. This may produce a response 
that is the result of the effect of psychological stress, which 
may diminish as the subject grows accustomed to performing the 
activity on a continuous or chronic basis. 

DR. FRANK: I did not emphasize it, but in speaking of hyper¬ 
reactivity, I posed the question: "Do subjects respond the same 
way when tested repeatedly?" I think you can define "repeated 
exposure" as you choose. 

I would agree that anxiety can influence response. We ought 
to test this notion as an hypothesis. I think anxiety is a par¬ 
ticularly important factor when you are testing a highly sensitive 
population, such as asthmatics. 


171 


DR. KNELSON; We specifically take into account the problem 
that has just been raised. We do not test for intra-subject varia¬ 
bility as Dr. Frank suggested, but at the Health Effects Research 
Laboratory we try to control it as a variable. 

One of the most important parts of our experimental design is 
the training period, the habituation period of all the subjects 
prior to the onset of the experiment. This is the last hurdle that 
the test candidate has to pass before he can become a subject for 
experimentation. During this period, we find out if the subject is 
capable of becoming a reasonable habituated, trained individual in 
the environment we expect him to participate in for a few hours or 
a few days. 

We not only control for differences in response (we call it 
"training effects") the way I have described, but we also test for 
its persistence. Do the data on Monday differ from those on Tuesday, 
Wednesday, Thursday, and Friday? No, we have found that they do 
not. 


The first experiment we ever conducted here was with carbon 
monoxide. In that particular case, we designed a double-blind, 
crossover study that specifically addressed the question of whether 
the subject's performance was different on Friday than it was on 
Monday. I think the idea of testing this as a hypothesis is very 
interesting. I would suspect that we would have considerable amount 
of variance. 

DR. FRANK: I happen to think that many responses are char¬ 
acterized by a considerable amount of variance. You can define 
an experimental circumstance in such a way that you say, "I will 
eliminate variance by dropping all subjects who do not satisfy 
my definition of conformity." 

But in doing that, you may exclude some significant proportion 
of the population. I wonder if in some way — it might be very 
difficult -- we shouldn't begin looking at the excluded proportion 
of the population as well. 

DR. HIER: The variance within a subject could be so-called 
stochastic variance, too; that is, the subject's response could 
vary randomly from day to day. To account for random daily varia¬ 
tion, we take repeated measurements and average out that kind of 
variability. If you want to introduce a specific variable, for 
example, anxiety, you introduce particular conditions that might 
exacerbate anxiety in one setting or another, so that it becomes a 
cross-condition effect. 


172 


But I am concerned that variability from one time period to 
the next is not being ascribed to strict experimental conditions -- 
that subjects are being subjected to more or less anxiety, to more 
or less training effect. But even after you control for all these 
variables, you still must contend with stochastic variability. 

The important thing is to take repeated measurements. 

DR FRANK: I would like to respond to Dr. Hier. In the 
typical experiment, one or perhaps two measurements of fuctional 
P^^^^ster are taken, and then an animal or human subject is exposed 
for a period of hours, followed by one or two measurements taken 
during or at the end of the exposure. My impression is that this 
procedure is extremely thin ice on which to characterize: one, 
the baseline function; and two, the changes that may be imposed by 
the stimulus you are applying. We very often stretch the data 
beyond the weight it can really support. 

DR. BENIGNUS: By "thin ice," do you mean the paucity of 
measurements taken? 

DR. FRANK: That is right, because the few measurements we 
make do not truly characterize the response during the period 
under study. 

DR. BENIGNUS: Two measurements are not very much. 

DR. OTTO: Just a quick follow-up on what you are saying. I 
agree very much with the comments about how to deal with sta¬ 
tistical variability, but there are problems with using a repeat¬ 
ed measurement design. For instance, if you are dealing with a 
chemical agent, you may be considerably limited by a repeated 
measurement design because the chemical's cumulative effect may 
thwart your attempts to obtain responses at the baseline level. 

In short, responses may be modified by cumulative effects. 

You may decide to wait three or six months to take another 
baseline measurement, but by that time numerous factors far beyond 
our control have changed—the temperature, the climate, the indivi¬ 
duals' home lives, or the subjects may no longer be attending 
school. These are particularly strong variables that we have had 
to face when dealing with the student population. 

DR. FRANK: These are highly complex experiments, and unless 
you have a hypothesis that you can test plausibly, and unless you 
pay real attention to this problem of describing the functional 
parameter before and after you intercede, you are going to end up 
with ambiguous data, which often happens in this field. 


173 


DR. OTTO: The importance of the initial finding may be much 
greater than later findings because the subject's tolerance to the 
test substance may change. The strength of the response is going 
to change and become much weaker. 

So, I am not so much worried about the importance of the 
initial changes that are observed. In fact, sometimes with carbon 
monoxide, we suspect that response changes may be an effect that 
occurs very early at very low levels -- that the organism is able 
to adapt almost immediately, say, within 20 to 30 minutes; and, if 
you do not catch the response as it occurs, you miss it forever. 

It is a real problem. 


174 


statement 


Bernard E. Statland, M.D., Ph.D. 
Department of Pathology 
University of North Carolina 


I would like to discuss the general problem of intra-individual 
variation of laboratory results. Intra-individual variation is 
the variation in results that one would note over time in one 
individual. This problem should be of great interest to all investi¬ 
gators studying the effects of environmental stresses on humans. 

So often investigators use mean changes in a group of individuals 
rather than looking at a person as his own control. Since many of 
these stresses of the environment will evoke a significant change 
within an individual, but not for a group as a whole, it is perti¬ 
nent to understand the expected sources of intra-individual varia¬ 
tion. As soon as we have an understanding of the sources and 
magnitudes of the expected intra-individual variations, we will be 
better equipped to handle the experimental problem. 

The major sources of intra-individual variation of laboratory 
results (and also most other variates which we measure in individ¬ 
uals) can be grouped into three types: 

1. Analytical variation 

2. Variation due to preparation of the subject 

3. Variation due to temporal considerations when obtaining 
a specimen 

Figure 1 schematically presents the source of analytical 
variation. The analytical variation can be divided into two types: 


175 





176 


Figure 








































the preinstrumental sources of analytical variation and the 
instrumental sources of variation. The preinstrumental sources 
of variation in results determined on a specimen of serum 
would include the venipuncture procedure itself, the filling of 
the tube(s) of blood, the transportation of the whole blood speci¬ 
men, the centrifugation step, the variation occurring while the 
serum sits on the clotted cells, the decanting of the serum 
supernatant, the storage of the serum specimen, the freezing 
and thawing of the specimen, and the processing of the specimen 
prior to the specimen entering the instrumental station. The 
instrumental sources of variation in the case of laboratory 
results obtained on a serum sample include the dispensing of the 
specimen, the uncertainty in the temperature during which the 
analysis is performed, and the spectrophotometric uncertainty, 
etc. Most approaches of quality control of the analytical variation 
are truly only monitoring the instrumental phase and not the pre¬ 
instrumental phase of the analytical procedure. Obviously, the 
intra-individual variation in laboratory results obtained on an 
individual will always include the analytical sources of variation. 
The analytical sources of variation will be the sum of the within- 
batch and the batch-to-batch variations. 

The second major source of variation is that due to the prep¬ 
aration of the subject. Subject preparation includes all those 
factors done to the individual or by the individual independent 
of the pathological process (or environmental stress) that one 
is investigating. Examples of such factors are prior exercise, 
previous diet, ethanol ingestion before specimen collection, 
posture of the subject, and tourniquet application time. 

The effect of exercise on serum enzyme values can be appreci¬ 
ated from the information seen in Figure 2. In this figure, we are 
depicting the percent change from baseline values in four subjects 
at various hours after a one hour exercise stress. The four sub¬ 
jects were males who underwent a 1 hour game of paddleball. At 
1 hour, 5 hours, 11 hours, 19 hours, 29 hours, 43 hours, 53 hours, 
and 67 hours after the stress, specimens were obtained from these 
subjects. The activity values for the enzymes creatine kinase (CPK), 
aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and 
alkaline phosphatase (AP) were determined on the serum specimens. 

The values were compared with baseline values (those obtained prior 
to the exercise stress). As noted in Figure 2, the mean creatine 
kinase values were 120% above baseline at 11 hours after the stress. 
The AST and LDH values also were elevated significantly. CPK, AST, 
and LDH are all enzymes present in muscle. Alkaline phosphatase is 
not present in muscle to any great degree. This enzyme showed very 
little change after the exercise stress. 


177 


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HOURS AFTER EXERCISE STRESS 


67 


Figure 2 



HOURS AFTER ETHANOL INGESTION 


Figure 3 


178 

























































We evaluated the effects of ethanol ingestion on nine healthy 
subjects. The subjects had baseline values determined for the 
serum enzymes AST, ALT, LDH, creatine kinase (CK), gamma glutamyl 
transferase (GGT), and AP. The ethanol stress consisted of 0.75 
grams of ethanol per kg of body weight ingested on three separate 
evenings. At 15 hours, 36 hours, 60 hours, and 100 hours after 
the third evening of ethanol ingestion, specimens were obtained 
and determined for the enzymes depicted in Figure 3. The most 
impressive change was noted for serum GGT. The mean increase in 
GGT was approximately 25% at 60 hours after ingestion. 


We examined the effects of posture on a number of serum analytes 
in 11 healthy subjects. These healthy subjects, all male aged 21 
to 24 years, had blood obtained both in the supine position (lying 
horizontally for one—half hour) as well as in the erect position 
(standing for 15 minutes and sitting 1 minute before venipuncture). 

As noted in Figure 4, the serum proteins, analytes bound to proteins, 
and enzymes were significantly increased. The bars in Figure 4 
represent the percent change going from the supine to the sitting 
position. In the case when such a change was significant, the bars 
are stippled. 

The third major source of intra-individual variation is that 
variation due to the effect of time of specimen collection. The 
temporal considerations can be divided into the within-day (hour- 
to-hour) and day-to-day changes. I will concentrate on the day-to- 
day changes. 

Figures 5, 6, 7, and 8 represent the concentration values for 
serum thyroxine, serum cortisol, serum triglyceride, and serum 
cholesterol in each of four healthy subjects. The subjects are 
labeled number 3, number 5, number 7, and number 8 in these figures. 
Blood was obtained at the same time of day after the subjects were 
in the sitting position. The posture and tourniquet application 
time were standardized. As noted in these figures, the intra-individ¬ 
ual variation for thyroxine was greater than the inter-individual 
variation. However, for the constitutents serum cortisol, serum 
triglyceride, and serum cholesterol, the intra-individual variation 
was much less than the inter-individual variation. 

The relationship of the intra-individual (within subject) to 
the inter-individual (subject-to-siibject) variation can be appreciated 
for the values of alkaline phosphatase activity in the serum of four 
healthy subjects. Figure 9 presents the values obtained on each of 
6 days during a 10 day period for four healthy volunteers. It 
is obvious that the subjects maintain their values for alkaline 
phosphatase in a very narrow range during the course of the study. 


179 


SODIUM 
POTASSIUM 
CALCIUM 
CHLORIDE 

PHOSPHATE 
UREA 

CREATININE 
TOTAL PROTEIN 
ALBUMIN 
IRON 

URIC ACID 
TOTAL LIPIDS 
CHOLESTEROL 
AST 
ALT 

ALK. P'TASE 
ACID P'TASE 

0 +5 +10 +15 

PERCENT CHANGE 


1 1 1 1 

] 

1 1 I 1 

1 1 1 1 







] 


















1 1 J 1 1 1 1 1 1 1 I'l 1 ■ 

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Figure 4 












































































































T 


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2 


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4 5 6 7 8 9 

DECEMBER 1975 


-I -1_I 

10 II 12 


Figure 5 



Figure 6 


181 


->)00 












Note that we are using arbitrary units rather than international 
units for alkaline phosphatase. 

Figure 10 depicts the ranges for alkaline phosphatase for each 
of fourteen individuals studied over 10 days. Specimens were 
obtained at 8:00 in the morning. They were analyzed in one batch 
at the conclusion of the study in order to decrease the magnitude 
of the analytical variation. In such a manner, we would only have 
to deal with the within-batch variation and not the batch-to-batch 
analytical variation. 

Figure 11 shows analogous information for the concentration 
values of the serum complement C4 values. Once again, we see that 
the individual maintains a much narrower reference region than 
does the group of individuals. 

The conclusions drawn from our studies thus far on the intra¬ 
individual variations or serum constituents are the following: 

1. Under conditions in which the analytical variation and 
the variation due to the preparation of the subject are 
minimal, the intra-individual variation is often much 
less than the inter-individual variation of mean values. 

2. When the intra-individual variation is much less than 
the inter-individual variation, it does make sense to 
use a subject's baseline values as his own control. 

When electing to use a person as his own control, there are 
certain issues that must be taken into account. The first issue 
is deciding on the appropriate biological model of time-series 
that a value is expected to follow. Two major models have 
been composed: the homeostatic model and the random walk model. 
Figure 12 illustrates the homeostatic model. In this model it 
is assumed that a subject has a mean value below and above which 
all values should fall. The variations from the mean are taken 
into account in order to ccxnpute a prediction interval within 
which the next value should fall. In Figure 12, we are examining 
four values of serum iron in a healthy subject. The fifth value 
should be expected to be the mean of the four. The width of the 
prediction intervals is dependent upon the standard deviation of 
the previous four values. 

In the random walk model (see Figure 13) the next value in a 
series of values should most likely be the most previous value. 

In Figure 13, we are looking at the same four serum iron values 
seen in Figure 12. The prediction interval, however, is 8.2 to 21.1 
for the 95% prediction interval as compared to 10.7 to 24.6 for the 


182 


homeostatic model* It is quite obvious that one must choose a 
model of biological time-series before being able to evaluate the 
width and the location of the prediction interval. 

When using a person's values as his own control, the analytical 
variance plays a very important role in the width of the prediction 
interval. The relationship of the analytical variance to the biolog¬ 
ical variance is depicted in Figure 14. This figure represents the 
relationship of the percent increase in intra-individual variation 
due to analytical error to the ratio of the analytical variance over 
the biological variance. When the ratio of the analytical variance 
to the biological variance is 1.0, one would expect a 42% increase. 
When the analytical variance to the biological variance is 4.0, 
the expected increase is greater than 120%. It had been recommended 
that the analytical variance to the biological variance ratio be 
no greater than 0.25. In this latter case, the percentage of 
increase would be approximately 12%. Such a guideline might be 
very important in prospective clinical studies as well. 

In conclusion, I have discussed the various sources of intra¬ 
individual variation that we as clinical chemists must deal with. 
However, the intra-individual variation has much wider applicability 
than just to clinical chemistry. It should play a role in monitoring 
a number of variates including blood pressure readings, respiratory 
function tests, and other parameters that are followed over time. 
Since more and more investigators are using a subject's previous 
values to evaluate the effect of various stresses, the elements 
going into the intra-individual variation should be noted. 

The work I have presented here has been done in collaboration 
with my colleague Dr. Per Winkel who is presently at the Finsen- 
institutet in the Department of Clinical Chemistry in Copenhagen. 

This work has been supported in the main by the Danish Research 
Council, departmental funds from the University of Minnesota, and 
departmental funds from the University of North Carolina, Department 
of Hospital Laboratories. 


183 



400 



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2 


j_I_I_I_I_I_I_I_I 

4 5 6 7 8 9 10 II 12 

DECEMBER 1975 


Figure 7 



DECEMBER 1975 

Figure 8 


184 



















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185 


Figure 








RANGE OF ACTIVITY VALUES OF ALKALINE 
PHOSPHATASE IN SERA OF FOURTEEN HEALTHY 


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ALKALINE PHOSPHATASE 
(ARBITRARY UNITS) 
























































SERUM IRON /j mol/liter 


PREDICTION OF SERUM IRON VALUE IN 
HEALTHY SUBJECT USING HOMEOSTATIC MODEL 



Figure 12 


187 















SERUM IRON /j mol/liter 


PREDICTION OF SERUM IRON VALUE IN 
HEALTHY SUBJECT USING RANDOM WALK MODEL 



Figure 13 


188 















PERCENT INCREASE IN INTRA-INDIVIDUAL VARIATION 
DUE TO ANALYTICAL ERROR 



Figure 14 


189 











1 


I 


■ % 






Discussion 


DR. BROMBERG: Apparently, there are many sources of what in 
the first approach we might consider as noise. However, part of 
this noise apparently is not noise. It is a response to other vari¬ 
ables that are not adequately controlled. So, in experiments, 
the researcher tries to look at some of these variables. For 
example, muscular exercise unfortunately has some prolonged effect 
on certain enzymes. 

Other sources of variability apparently remain ccxnpletely 
undiagnosed, and we call them noise. Evidently, there are two kinds 
of noise, some of which we may understand and try to control in our 
experiments, and others that are beyond us, which we have to live 
with. 


The worse the total noise, the more limited we are in looking 
for subtle or small effects on signals. How do we deal with that 
problem? How do people like Dr. Horvath, Dr. Frank, and Dr. 
Battigelli—all members of the panel who are, in fact, very much 
concerned with making measurements in man and picking up relatively 
small effects—deal with this problem in a practical sense? 

In addition, how small are the effects that we ought to look 
for? Is there some limit we ought to impose on ourselves and not 
attempt to look for effects beyond that limit? The experimental 
situation is too complex for us to eliminate a certain residual 
level of uncertainty. Perhaps we ought to look only for fairly 
gross effects. 

DR. PENGELLY: I don't know whether we were ahead of the 
clinical chemists in recognizing this problem of unidentifiable 
fjQise, but when we designed protocols for the ozone experiments 
performed in the late 1960's, it was clear to us that we could not 


191 


use a population standard for what we would expect. We did not 
pick a population standard for FEV^* and then compare a response 
of an individual. 

It was clear that we had to peform what we called sham experi¬ 
ments, in which we allowed for whatever variable that was going to 
occur. We changed only one variable in the experiment, the expo¬ 
sure to ozone. Then, we repeated the experiment in exactly the 
same way over exactly the same time period with exactly the same 
individual and compared the two experiments. 

I think this approach has long been the traditional approach 
to exposures of human subjects to environmental contaminants of 
this type. Moreover, I think Dr. Frank was very impressed with 
the results of the controlled experiments conducted at the facility 
here—how the individual variability is quite small and how well 
individuals have been characterized. I think that the lesson of 
the significance of intra-subject variability has been learned in 
this area. 

DR. BROMBERG: But you have not controlled for the effect of 
time in your procedure. You did an experiment on day one, and you 
made some assumptions as to how long you had to wait to do a valid 
experiment, a sham experiment, and then you conducted that sham 
experiment several days of weeks later. You were still left with 
some potential for variability. 

DR. PENCELLY: I think the important point was to compare the 
individual against himself. 

DR. HORVATH: In one sense, I disagree with you. Dr. Pengelly. 
In the first place, I believe that we all have an idea of how to 
handle intra-subject variability, but I think Dr. Statland's 
observations indicate very clearly that this is all a figment of 
our imaginations. It leads us into an uncomfortable situation of 
evaluating the effects of anything on a human organism. 

One of the points I made in my presentation was that the 
investigator has to prepare the subject. Dr. Statland has empha¬ 
sized this point. There are three variables that we have not 
considered: first, the effects of changes in posture, which can 

result in a 16-20% change in plasma volume; second, the change in 
biorhythm, which we have ignored to some degree; and third, the 
most important factor--what happens to an individual on day A and 
how long does he have before he fully recovers? I repeat again the 


♦forced expired volume in one second 


192 



statement I made, because I think most people have not looked at 
all the literature in this field, and I am sorry to say that I did 
not know about your work either. 

It is certainly obvious that it takes many days to recover 
from any kind of strenous activity. Recall Dr. Statland's data. 

Out of 10 marathon runners, only two were able to complete a 
short, 5 mile race 5 days after they had run a 2-1/2 hour marathon 
race. Moreover, the two subjects who completed the short race 
were unable to run it at the same speed they had run the 26-mile 
marathon 5 days earlier. It took almost 7 days for some of the 
blood parameters (hematocrit, for example) to return to normal. It 
appears to me that some of the effects we are looking at are very 
definitely hidden by our failure to know exactly what has happened 
to the subject. 

I am just as guilty as anybody else because I accepted the 
same premises you did. Dr. Pengelly. But I am convinced now, 
after what we have been doing the last 2 years in this area, that 
we have made horrible mistakes. We have got to use an entirely 
different approach in our testing. 

DR. BROMBERG: Dr. Horvath, let me ask you a question. 

Suppose I do an experiment where I compare vital capacity measured 
on day two after exposure to gas "x," to the vital capacity measured 
on day two following a double-blind exposure to scrubbed air. I 
find the exposure to gas "x" in four out of four subjects has 
apparently resulted in a reduction in the vital capacity of 5%, 
plus or minus 1%. Every single subject went down, but one went 
down 4%; another, 5%; another, 6%. Now, have I found anything? 

DR. HORVATH: Of course you have found something, but what do 
your findings mean? I think everyone has done about the same sort 
of thing. However, the point is do your findings represent anything 
in terms of what has happened to the subject? For example, one of 
the things we did with ozone was to show very clearly that the 
greater effect is observed immediately after the individual has 
finished exercising. If you waited half an hour or 15 minutes, 
the effect is less: that is, the decrement is smaller. 

I feel very strongly that we have missed the boat with regard 
to our approach. We have missed it because we still work on the 
basis of old-fashioned statistics; namely, we use "T" test for 
evaluating everything, and that is not a critical way to evaluate 
the test results. 


193 


I think we are in this same position right now. I just want 
to say that Dr. Statland made a very nice presentation because he 
brought out three important testing considerations; time, day- 
to-day position of the subject, and the effects of the studies 
done prior to the time the individual was used as a subject. 

DR. BROMBERG: You feel not that we have missed the boat, but 
that we have over-interpreted the boat? 

DR. HORVATH: Well, that is missing the boat. 

DR. BATTIGELLI: I would like to mention that Theodore Hatch 

said some 10 or 12 years ago when he stated that our ability 
to measure and to identify factors of possible injury far exceeds 
our ability to interpret the meaning of our measurements. He 
stated that at times we may vastly exceed our ability to interpret 
effectively what we can observe and quantify quite carefully. 

But indeed, I think the reply to the question we are discussing 
is what Dr. Statland and Dr. Horvath have presented to us, and what 
Dr. Frank and Dr. Pengelly have stre3sed--the proper design of an 
experiment. By proper design of experiments, I mean segregating all 
the significant variables (whether irrelevant or important) that 
may affect the detection or the observation of the effect. Once we 
accomplish that, we can proceed to the next step, which is to 
interpret change and/or effect. 

But in recent times, and this is probably what Dr. Horvath 
alluded to, all too often we have made interpretations based on 
crude designs, mixing into that process various factors so that 
the significance in the causation of the effect observed is lost 
or equivocated. 

DR. BROMBERG; What I think you are saying is that we ought to 
design our experiments better so that expert statisticians can help 
us obtain the absolute maximum from our experiments with the minimum 
chance of mistake. 

I would like to look at this issue a little bit differently. 

I would like to postulate that we have found a 5% change in some 
variable that may be of interest. But suppose we had a system of 
electrical resistors arranged in series, with a total resistance 
being the sim of all of the resistors. We tamper with one of these 
resistors, causing its resistance to change 200%. Yet, when we look 
at the overall resistance of the circuit we see only a small change. 
It turns out to be a definite change, but a very small one. And 
we wonder—what does this change mean? If we only focus on the 


194 


pertinent part of the system, we might then see that we had indeed 
uncovered a very, very big change. 

If I am right, this illustrates the importance of focusing on 
mechanisms; of trying to understand in detail what is happening, 
rather than being satisfied with an overall, very small effect and 
remaining uncertain. Does the response really mean anything? Is 
it biologically meaningful? Is it clinically meaningful, or is it 
only a trap? Is it due to poor design of the experiment? 

DR. BATTIGELLI: Granted, but don't you find that Dr. Statland's 
approach is exactly the right way to identify a mechanism? In other 
words, the statistician is not the only crucial person that can 
provide us with an adequate design. It is the epidemiological 
design that probably overrides or is as important as that factor 
or design that satisfied only medical adequacy. 

DR. HORVATH: I think it might be appropriate to have on the 
record that we are going through our usual 10 - or 20 -year cycle 
in research. I would like to point out that in 1966, the New York 
Academy of Science published an extraordinary review of papers on 
human variability. I think it would be to our advantage to read 
those papers again. I think we have forgotten what we intend to 
do and now we are back on that cycle of remembering again, which is 
nice to know that it takes ten years to do. 

DR. STACY: I would like to inject a note of heresy. Any 
physiological scientist who has been around for very long knows 
that there are many factors that comprise the results of any 
single measurement. If a researcher knows that a factor is going 
to influence his measurement, he controls that factor. Eventually, 
though, you have controlled for all the factors that you know 
about, and you are left with a stochastic residue with which you 
must live. 

But having controlled everything that you know about, you 
proceed with these experiments and use what statistics you have to 
get results and draw conclusions from the experiment. I think we 
are worrying too much about the fact that there are a lot of 
variables. Of course there are; we know that, so we design around 
them as much as we can. And what we can not design around, we 
treat exactly as we do in measuring average evoked responses. We 
know that there is a lot of noise, thus we take enough measurements 
to average out the noise. 

DR. HORVATH: But my point is that we do control all the 

0 s we remember, but we do not remember all the variables we 

should. 


195 


DR. STACY: That is true. 


DR. KNELSON: We might open up just one other area of discussion 
briefly, and that is the way all of us are used to handling the 
double-blind, randomized, crossover design where each individual is 
his own control. It has become almost a cliche in experimental 
design, but I think there is another aspect that we are missing, 
which we are beginning to examine. When we study 30 subjects under 
a set of environmental conditions (in this case, clean conditions), 
and if we have properly followed all the criteria Dr. Otto talked 
about in selecting these subjects, there is no reason to believe 
that our test subjects are not as representative of the universe 
that we are trying to estimate as the next set of 30 that we 
select, using the same criteria. 

We we study the next 30 subjects under the experimental 
conditions, we do not have the compounding variable of a person 
serving as his own control, but during that time he has experienced 
a set of environmental conditions that may have changed his control. 
So, using multivariant statistics where 30 subjects serve as a 
characterization of the universe that we are trying to estimate 
some parameter of, and then taking another 30 and using them in 
only the experimental situation, you do not go back to the old "T" 
test. 


I think we get some statistical follow-up at times there. We 
may also be getting a better representation of the population. In 
clinical medicine, frequently the population of concern is a single 
individual. That individual is the universe of concern. We are 
concerned about 200 million citizens of the United States. 

DR. HIER: I would like to expand on that. Dr. Knelson. The 
idea of using an independent control group can be important in 
that when you start, the subject who undergoes a "control" experi¬ 
ment is permanently altered; consequently, you no longer have a 
fair comparison if you use that subject as an experimental subject, 
too. 


You can counterbalance that by giving him an experimental 
control, but that takes a long time. You can have your cake and 
eat it too, in a way, by giving each subject a baseline run without 
experimental intervention, giving one group of subjects two baseline 
runs and the other group of subjects a baseline and experimental 
run. The baseline run that is given to one group of subjects, which 
is the next experimental line, serves as a control for individual 
differences. 


196 


Then you can subtract or use an analysis of covariance for 
each individual difference, for each individual's characteristics. 
That way you do not have to worry about the permanent alterations 
that occur every time you do something to a person. 

DR. STATLAND: You are right. You are about ten years ahead 
of clinical chemistry. But the reason why you are is that the 
concept of preventive medicine has only come about recently within 
clinical medicine. Basically, we have been very therapeutic in 
nature. We have looked at the disease after the cause. I think 
medicine is changing in general, not just clinical chemistry. 

The second reason we clinical chemists are now looking at the 
same issues as you is because our analytical procedures are now so 
much more precise and so much more accurate. We can do a glucose 
test today much more accurately than we could in the past. There¬ 
fore, the question is: With this extra analytical precision and 
accuracy, what are the other issues that we want to deal with, that 
we want to consider and control? 

Just a few comments about points that have been mentioned 
before. One of the concerns when you compare two groups of 30 
individuals is trying to define analytical variations. And, of 
course, that occurs within the subject as well. 

As you become more proficient in conducting experiments, you 
also may change certain things, for example, the number of baselines 
to have on the subject or the type of biological time series model 
that one must adopt. 


197 


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statement 


L David Pengelly, Ph.D., P.Eng. 
Me Master University 
Hamilton, Ontario 


I am approaching this topic, "Special Considerations and 
Approaches," wearing three hats. My first hat is an electrical 
engineer. As an instrumentation engineer, which I was for many 
years with David Bates, I am concerned about the precision of all 
environmental and biological measurements. We had quite a lot of 
good discussion about this, and I think we could perhaps still have 
a little more. 

My second perspective is as a physiologist. I am concerned 
about the need for a broad testing approach, and in fact, we have 
already touched on some of the effects of biological variables. One 
variable that has not been mentioned, which I think is very impor¬ 
tant, is the age of the subjects. 

Racial origin, for example, may be a very important factor in 
test responses. The hormonal effects, such as the estrus cycle in 
females, is obviously a factor that should be taken into account. 
These variables have already been referred to. The question of 
whether you are measuring the right thing should also be included in 
the broad approach. One always has the suspicion that he may have 
overlooked a sensitive factor that should have been measured. 

Last of all, right up there on top, is my third hat—as an air 
pollution health effects scientist. I feel strongly that early stud¬ 
ies on the synergistic effects of pollutant gases and so-called inert 


199 


aerosols will be necessary to enhance the credibility of the chamber 
studies that we are conducting. 

Perhaps I might take issue with Dr. Frank on this point. Ob¬ 
viously, one should not begin this type of study with a "Let's see 
what happens" attitude. I think there is ample evidence that the 
aerosol particle is a very special vehicle for conveying pollutants 
to nasty places. 

I would now like to elaborate on these points. The first issue 
concerns the precision of measurements. In the early days, many of 
us used simple homemade chambers made of plastic and a few bits of 
angle iron. In Figure 1 note the high-volume sampler we used to 
measure suspended particulates, and that the subject is sitting at a 
desk. That is the sort of elementary approach we used. 

Figure 2 shows our pulmonary data acquisition system. It is a 
very simple acquisition system, but I think it is aesthetically more 
pleasing than the ones that you have here. It is capable of a 
certain amount of independent programming. I included these figures 
for historical interest, and to show you that we use a very simple, 
inexpensive approach. 

We cannot ccxnpete with the EPA in terms of throughput or in the 
detail of the meticulous studies you are capable of here at the 
Health Effects Research Laboratory. Consequently, I think that 
places a special responsibility on you for giving us the data on 
the studies you have performed. The tools that you are using-- 
computer data acquisition on pulmonary function performed—are by 
far sharper tools than the ones we have been able to use in the 
past. 


The fact that analytical variability has now been reduced af¬ 
fords us the opportunity to produce unique information on the vari¬ 
ability of baseline levels on which many pulmonary functions are 
based. The problem of variability and precision of measurements 
is one that you are in a very good position to attack and document. 

I suggest that it would be wise to document and analyze these 
baseline data formally for the rest of us so that we can have the 
advantage of your experience. In addition, I think you should very 
carefully establish the type of measurement protocol that you plan 
to follow. If you use a protocol that is not generally accepted, we 
need explanations as to why you think it is better. 

The second point I should like to examine concerns the choice 
of subjects. There are a number of factors that play an important 
role in sxabject selection. When choosing subjects, one must be con¬ 
cerned about the sources of known variability. The age of subjects 


200 



Figure 1 



Figure 2 


201 
















is one example. I am not completely convinced that it is sufficient 
to examine the response of young, normal, white, male subjects 
which, if one examines the literature today, represent by far the 
greatest number of human exposures to pollutant gases. I think it 
is very important that researchers be prepared to study a wide age 
spectrum—probably as wide as from seven to seventy years. 

Other factors of variability include the difference between 
smokers and non-smokers; the effects of cyclic, natural, and 
therapeutic hormones; and, perhaps even as has been suggested, the 
influence of diet. The studies done by Jack Hackney suggest that 
factors such as place of residence, and polluted or non-polluted 
environment, may very well play a role in variability.* For 
example, using gas for home cooking might be a very important 
determinant as to how a person responds to oxides of nitrogen. 

As a respiratory physiologist, I also suggest that the kind of 
pulmonary function test chosen is important. I think that the 
ciorrent use of the single-breath foreign gas dilution, the so- 
called "closing volume test," and the flow-volume curves done with 
air and helium-oxygen mixtures, could be useful adjuncts to a 
protocol. 

I am sure you have agonized over what sort of test would be 
the most useful and sensitive. I think the evaluation of changes 
in non-specific bronchial reactivity is also likely to be useful, 
but again, there is a limit on what you can inflict on test sub¬ 
jects . 


My last point is in support of what Dr. Bromberg has suggested. 
I, too, would like to make a plea for the study of mechanisms. I 
suggest that resources such as people who are able to interpret 
mechanisms would be a very useful adjunct to the operation of the 
Health Effects Research Laboratory. I think it is not enough to 
say that a given level of a given substance does not produce a 
specific effect of a certain class. If we are to gain insight into 
the lung's defenses, into other disease entities, if we are to get 
more output from these kinds of studies than just that output direct¬ 
ed towards standards settings, then we have to be in a position to 
shed light on the mechanisms. 


♦Hackney, J.D., W.S. Linn, S.K. Karusa, R.D. Buckley, D.C. 
D.V. Bates, M. Hazucha, L.D. Pengelly, and F. Silverman: 
of ozone exposure in Canadians vs. southern Californians: 
for Adaptation. Arch . Env. Health 32 (3): 110-116, 1977. 


Law, 

Ef fects 
Evidence 


202 






Discussion 


DR, OTTO: Obviously, the lungs are one of the primary sites 
through which air pollutants are ingested, but it seems to me that 
we have inordinately emphasized pulmonary function. I think the 
panel should discuss other organs that might be targets of air 
pollution effects. 

DR. BROMBERG: It is true that carbon monoxide is the noxious 
gas that is most often considered to affect other systems, and the 
lung is the portal of entry for carbon monoxide. Work with other 
gases has focused primarily on pulmonary effects. 

On the other hand, for ozone there is evidence that red cells 
are affected. In a more hypothetical vein, immunocytes present in 
the bronchus, which is associated with lymphoid tissue just under¬ 
neath the epithelium, may be affected. These immunocytes are local, 
but they do ccxnmunicate with the body's overall immune system. 

Other gases may cause changes in capillary endothelial cell 
function, which would result in more widespread changes in the 
circulation. These effects are a bit more remote and probably are 
not as attractive as topics for study as the pulmonary effects. 

The clinical side of the coin is that people die of lung 
disease or suffer from chronic pulmonary symptoms: consequently, 
lung function has received more attention than other, less directly 
affected sites in the body. I would like to know what other people 
think. 

DR. KNELSON: We should make it explicit in this discussion 
that we are addressing only a few facets of a large problem. Much 
of what we have talked about touches only the periphery of the air 
pollution testing program currently underway at the Health Effects 
Research Laboratory. In our laboratory, we invest as many resources 


203 


in the study of vitro cellular toxicity testing as we do in 
pulmonary function testing. For several years, we have had a 
relatively ambitious psychophysiology neurobehavioral program. We 
collect venous blood cells from exposed subjects and study the 
immune competence in these cells ^ vitro . We also conduct rather 
aggressive metabolic tests on these subjects. 

DR. HAZUCHA: I would like to comment on Dr. Otto's remark. 

It is true that we are concerned with pulmonary function because 
it is a primary target, and I have no doubt that different pol¬ 
lutants will affect the systems within the body. But if we 
compromise in measuring pulmonary functions, we will have to be 
prepared to compromise in studying other systems. 

When I measure vital capacity, I do not care if the subject 
drinks a glass of water or eats a sausage in the morning. If, 
however, I want to measure some level of enzymes, I certainly will 
be concerned with what the subject has eaten. The more sophisticated 
test I use, the more I have to be concerned with factors such as 
the subject's posture or the time of day, or any of those factors 
mentioned by Dr. Statland earlier. 

DR. KNELSON: I would like to amplify what Dr. Hazucha is 
saying. We have already designed experiments that are impossible 
to conduct. The interests of the psychophysiologist, the interests 
of the clinical chemist, the interests of the cardiologist and the 
pulmonary physiologist are converging on a group of subjects that 
allows us to write a protocol we can never implement. As a result, 
we sit back and say, "Well, which variables can we afford to 
measure at this stage; which ones are we going to have to put off 
for the next experiment?" 

DR. BENIGNUS: I have heard several of you comment that theo¬ 
retical work, backup work on the mechanisms of the effects we 
observe, is important and necessary. Because it contributes to 
the body of knowledge about physiology, such work is not only 
necessary from the academic point of view, but also from the point 
of view of credibility. 

I do not, as a scientist, have much faith in results that show 
only a decrement in some kind of performance—for example, the dose 
response curve. As a scientist, I would have much more faith in 
results that explain to me the mechanisms that produce the effects. 
Work of this type is not just a matter of contributing to the 
academic pool; it is a matter of gaining credibility in the 
scientific community. 


204 




DR. HAAK: To amplify that. Dr. Pengelly mentioned that perhaps 
our activities are directed toward setting standards. I believe 
that when our recommendations for air quality standards, which may 
be based on the 5% decrement in pulmonary function that Dr. Bromberg 
mentioned, are tested in court, the judges will require some 
mechanistic formula to interpret how many millions of dollars our 
recommendations will cost. Scientists from industry will argue 
that a 5% decrement does not warrant the expense of millions of 
dollars. Other scientists will be asked to explain what impact a 
5% decrement will have on public health. 

As long as the mechanism is not clear, the court and the judges 
will be unwilling to make a multi-million dollar decision. The 
issue will be a stalemate. The scientists will be sent back to the 
laboratory to do more research to support their recommendation of a 
particular standard. And that research will have to be based on 
the expected mechanism of the pollutant at issue. 

DR. OTTO: Allow me to cite one example that puts this issue 
into perspective. We have not said very much about our neuro- 
behavioral research. In fact, the results of our studies, which 
in some cases reveal positive findings, have had virtually no 
impact on standard setting in this country, even though we have 
been collecting data for five years. 

One of the reasons that we have not had any impact is that 
when we measure brain waves, for example, and we notice an increase 
in a given component, we do not know what the underlying mechanism 
is for the change in that component. Therefore, our friends in 
Washington, who have to evaluate this data, say, "So what? You 
showed a change in the brain wave function; I can pick up my cup 
of tea and joggle it around and show changes there, too, but 
what is the functional significance? Until you can tell me the 
mechanism and what its functional significance is, I really do not 
know how to evaluate your data." The mechanisms must be described 
before we can really interpret the effects that we observe. 

DR. BROMBERG: I do not know whether I know David Bates' point 
of view well enough to speak for him, but my impression is that he 
would say, "If you have demonstrated a reproducible effect, that 
effect speaks for itself. The burden is on those who would deny 
the significance of that effect to prove that it has no significance. 
To those individuals, I simply say, 'Well, I saw something happen, 
and if you cannot disprove that it happened, then I have proved my 

case.'" 


What about that point of view? Do you deal with this at all. 
Dr. Frank, in thinking about what it is you want to measure? 


205 


DR. FRANK: Yes, I do. I have stated that dose response 
relationships have considerable impact in this field. Let's face 
it—they do. Ultimately one of the issues that we should address-- 
and this is kind of circular—is that basic research, dose response 
relationships, animal toxicology and epidemiology all feed into 
one another. To the extent that any one of these elements is 
isolated, you can forget about it, if it cannot be drawn into the 
entire picture. If animal toxicology and clinical research do not 
inform and influence the design of epidemiologic studies, then we 
are spinning wheels. I think we all agree on that. 

My bias is toward studies of mechanisms. This is what fasci¬ 
nates me. For example, we are in the process of trying to find a 
basis for what may be the vulnerability of certain individuals in 
the population to sulfuric acid. There is a good analytical 
chemical basis for this notion, and I think it could be tested and 
that such a test would not only be informative, but also great 
fun. 


As scientists we ought to anticipate being confronted with 
the problem of how to relate our observations to some remote 
entity, such as lung disease, or even "public health." We should 
be prepared to say, "I have made an observation and I do not 
understand it, but I think it has the following implications." 

Then we should begin to test the hunch. 

We should not say, "Here's my observation; it is an effect." 
Implicit in that statement is the notion that all effects are bad. 

I do not think they are. I have seen some data on dose response 
relationships to ozone obtained from an extremely good laboratory. 
The data were presented as evidence that there was an adverse 
effect, beginning at about 0.3 ppm of ozone. My reaction to the 
data was that it was reassuring that there was virtually no adverse 
effect in the subject when he was breathing at rest. In my judg¬ 
ment, the deviation from zero was almost trivial; it was within 
the variance of the measurement in the population. 

DR. BROMBERG: It is hard to know what to do with small 
changes. One man's artifact is another man's Nobel Prize. A small 
change may be a very significant piece of information if we only 
knew how to isolate it, to focus on it, and to amplify it and 
understand it. 

DR. FRANK: I couldn't agree more. 

DR. BROMBERG: On the other hand, a small change may really 
be nothing. 


206 


DR. FRANK: Again, I couldn't agree more. What is an ap¬ 
parent certitude today may change radically in its implications 
tomorrow. We do not have final truth on anything, and there is 
always the danger of over-interpreting data. But we do end up 
with a lot of curiosities, and it seems to me that they get in our 
way. The curiosities exist, but we avoid exercising judgment 
about them. 

It would be ideal if we could eliminate all environmental 
stress, but we are not about to do that. What we have to try to 
do is exercise a certain amount of judgment about how much is 
tolerable. 

DR. HORVATH: I would like to make one facetious comment and 
one serious comment. The facetious comment has to do with the 
"beneficial effects" of ozone exposure. My reaction to that is as 
follows: one of the things that we discovered was that the maximum 

aerobic capacity—in other words, the capacity of a man to work at 
a sustained level--seems to be reduced because of ozone exposure. 

I say that may be beneficial because it may prevent all of us from 
becoming over-worked; so, if we are exposed to ozone, we may 
actually be benefitted by it. 

My serious comment concerns Dr. Pengelly's important sug¬ 
gestion; namely, that we are ignoring the effects of age. The 
only studies I know of that contain any data on age were the 
studies we did with carbon monoxide. We looked at young Caucasian 
males, middle-aged Caucasian males, and we looked at smokers and 
non-smokers, depending on whether they had smoked at least one 
pack of cigarettes a day for a couple of years or for 16 to 17 
years. We noticed differences among these groups. 

But that is the only study on age groups that I know of. We 
have ignored the effects of age for all the other pollutants, and 
I feel strongly that the age factor must be taken into account 
because we do know there are obvious changes that occur in indivi¬ 
duals as a consequence of age and as a consequence of sex. 

Age and sex have to be involved in any consideration we give 
to what happens to the population. After all, 10.9% of the 
population in the United States is over the age of 60. That is a 
huge percentage of our population. The point that Dr. Pengelly 
did not bring up, however, which annoyed me considerably, especial¬ 
ly since in my laboratory we have some very strong people who are 
of the opposite sex, was the influence of sex hormones. He 
hinted a little bit, but I think we have to consider the striking 
(jf 0 i;‘ 0 nces between males and females. We are completely ignoring 
53% of our population. Every time I ask someone if they support 


207 


studies on females, they look at me and say, "Well, females are 
females." They are, indeed, and from the standpoint of being good 
subjects, they are much more attractive than males. 

We are also ignoring the elderly. When you talk about pol¬ 
lutant effects on humans, what groups are concerned? Who dies? 

It is not the young Caucasian male and female. It is the old 
Caucasian male and female, and we have paid no attention to them. 
This is one of the real difficulties that I find with all of the 
experimental work that is being conducted on air pollutants. We 
will have wasted a great deal of money if someone does not start 
to support studies involving females and the elderly. The cost 
benefit problem is of no importance if you relate it only to young 
Caucasian males. 

The factor of race is another problem that we have ignored. 
Studies suggest that the responses of other races to environmental 
stresses are different from the responses of Caucasians. We must 
seriously consider the factors of age, sex, and race. We must 
move quickly to incorporate people from these groups into our 
studies, even though it is not easy to recruit subjects from the 
population at large. 

My feeling is that no human organism can survive if he isn't 
under some environmental stress, and I do not think we can remove 
stresses from the organism. I am not sure that we can benefit by 
studying ozone or dioxides as stresses, but I do think that we 
have to have a certain degree of stress. 

Before we decide whether or not these minor changes that we 
have been recording are bad for us, I think we must ask ourselves, 
"How much do we need of this stress in order to survive?" 


208 


statement 


Mario C. Battigelli, M.D. 
School of Medicine 
University of North Carolina 


I shall briefly attempt to offer some encouragement to consider 
human experimentation as a legally, socially, academically, and 
medically acceptable endeavor. 

Experiment is such a ccnimon event in life--certainly it is 
common in many professional habits and commitments--that maybe 
something is lost by using the term. Some of you may remember 
the lovely poem by Emily Dickinson that ends something like this: 
"Experiment to me is everyone I meet." 

Some of you may remember the well-known British cardiologist 
who stated that any time a physician embarks on a treatment of a 
patient, he is conducting a clinical experiment. Justice Holmes 
remarked that "All life is an experiment; the best test of truth 
is the power of the thought to get itself accepted in the competi¬ 
tion of the market." 

"A test, a trial, a tentative procedure" is the dictionary 
definition of experiment. The thought process that we have accept- 
ted in embarking on experimental work will be exemplified by 
discussing our experience in byssinosis.* I shall from the outset 


*Byssinosis is a form of pneumoconiosis due to the inhalation of 
cotton dust. 


209 



define that we are not testing the entire pathogenesis of bys- 
sinosis, but only a very small aspect of it--the acute ventilatory 
response to calibrated clouds of cotton dust. 

Whenever we deal with cotton dust, we face a complex, hetero¬ 
geneous mixture of particles that may be derived from contaminat¬ 
ing dirt or from various parts of the cotton plant--the fibers, 
the shell or pericarp, the bracts (small leaf-life appendages at 
the base), the stem, and the leaves. 

Exposure to cotton dust is associated with the development of 
a syndrome we call byssinosis. This syndrome is an airways response, 
a sort of asthma, which is associated with well defined symptoms 
that have a characteristic cyclic expression, at least at the be¬ 
ginning of the natural history of the disease. 

The subjective syndrome is part of a phenomenon that may be 
objectively identified as a respiratory decrement, a respiratory 
loss following exposure to dust, well described by the spirogram. 

We also recognize that not all of the individuals exposed to 
cotton dust come down with a significant response, and that the 
proportion of those affected increases in proportion to the in¬ 
tensity of the exposure. It has also been ascertained that indi¬ 
viduals not used to the occupational exposure may, on exposure to 
sustained concentration of dust, exhibit the symptoms, as well as 
the signs of the cotton dust effect. 

In any area of knowledge, there are certain aspects that are 
out of focus, incomplete, erased, or totally missing. One of the 
aspects that we thought interesting was to verify how specific was 
the acute ventilatory response related to other conditions that we 
distinguish from byssinosis. What is the dose-relationship of the 
specific response, and the specific agents causing these responses 
in patients, volunteering as subjects, or in normal healthy indivi¬ 
duals who are free of disease and unexposed. 

The primary justification for collecting information on dose- 
response relationships is that such information is helpful in 
formulating appropriate medical management procedures, including 
removal from exposure, reassignment, relocation, retirement. 

Hence, experimental exposure may assist in defining guidelines for 
this type of decision. There is more to it. 

We considered several questions as clinically significant to 
our study. First, is there a minimal concentration and/or duration 
of exposure that is effective in identifying the specific, segre¬ 
gated ventilatory response, whatever the relationship of this may 


210 


be to the whole syndrome? Second, are there any specific character¬ 
istics of reactivity (such as symptoms or objective ventilatory 
parameters) that can be defined and perhaps related to the patho¬ 
logical background of each subject? Third, can these definitions 
of reactivity characteristics be used to formulate pathogenetic 
considerations? 

The fourth question is, are there specific components or 
characteristics of the exposure, the nature of the dust, that can 
be identified as most injurious and therefore necessary to the 
understanding of the natural history and the pathogenesis of the 
disease? 

In designing and executing the experiments, considerations of 
safety are quite straightforward. Our continuous monitoring pro¬ 
gram is maintained by assaying dust level continuously and by 
having a physician exposed to the same conditions as the subjects, 
in the exposure room. 

The nature of the response, at this concentration, is limited 
and invariably reversible. We must recognize that the true experi¬ 
mental value to these activities is simply that we duplicate what 
happens in the real world within total uniformity and continuous 
control. 

In doing so, we find justification in trying to remove the bad 
connotation from the word "experiment." This term conjures visions 
of vivisection, which, of course, excites the minds of those who 
tend to see greater risks than actually are warranted in these 
circumstances. 

I would like to pass on this word of encouragement, quoting 
from no one less than Jacob Bronowski, who said, "We live surrounded 
by the apparatus of science, the diesel engine, the experiment, 
the bottle of aspirins, and the survey of opinion. We are hardly 
conscious of that, but behind that, we are becoming conscious of a 
new importance in science. We are coming to understand that science 
is not a haphazard collection of manufacturing techniques, carried 
out by laboratory dwellers with acid-yellow fingers and steel-rimmed 
spectacles and no home life. 

Science, we are growing aware, is a method and a force of its 
own, which has its own means and style, and its own sense of 
excitement."^ 

One may wish not to call an experiment an experiment; let us 
call it a justified verification of an hypothesis, but the fact is 
that that type of endeavor is here to stay. We are bound to conduct 


211 


experiments, and perhaps a safe beginning is with a restatement, 
according to what Socrates suggested, "The beginning of wisdom 
is the definition of your own terms."^ I suggest this for your 
own activities. 


REFERENCES 

1. Holmes, Jr., O.W.: Abrams v. United States, 250 U.S., 616. 

2. Bronowski, J: Common Sense and Science, Heinemann (ed.), 1951. 

3. Vitae Philosophorum. Cited by Diogenes Laertius (Long, H.S. 
ed.). Oxford Univ. Press, 1964. 


212 


Discussion 


DR. BROMBERG: Yesterday Dr. Bates said that he thinks certain 
experiments are best conducted in the environment where the problem 
actually exists. If, for example, you want to study the long-term 
effects of sulfur dioxide, perhaps the best place to do so is in 
the work setting of lead smelters, and not attempt to study the 
long-term exposures in a chamber. 

Perhaps the smaller, better controlled studies that we do in 
the laboratory should be viewed in this context. As long as we do 
not exceed the exposure levels that are occurring in, and are accept¬ 
ed by, our industrial society, perhaps we should consider the real 
environment as a standard of reference for what we should permit 
ourselves to do or not to do. 

DR. CRIDER: If you use the workers in a particular industry 
as your subjects, you may be omitting a large percentage of people 
who may be susceptible to a particular agent. Individuals who 
can survive potentially harmful environments tend to continue to 
work in them; those who cannot, do not. I think we would have to 
be careful in conducting the type of studies that you suggest, and 
in selecting subjects for them. 

DR. BROMBERG: I am not saying that one has to go into the field 
and find individuals and study their responses to controlled lab¬ 
oratory exposures. I am just saying that our society has indicated, 
for the moment, its willingness to tolerate certain levels of 
human exposure. By using society's willingness to tolerate exposure 
as a standard of reference, perhaps the much more careful approach 
we use in the laboratory is really quite defensible. There may be 
another perspective from which to view our experiments other than 
the almost frightening portrayal suggested by moralists, chairmen 
of human use committees, and doctors of jurisprudence. 


213 


Dr. Battigelli did not really discuss in detail any of the 
work that he has done, but many of his subjects are not people who 
are occupationally exposed to cotton dust, or who have any history 
of byssinosis. They are people who have well-defined, chronic ob¬ 
structive lung diseases of more common varieties, but who are 
nonetheless willing to be exposed to cotton dust. They are ex¬ 
posed along with the experimenter himself, who sits in the chamber 
with the subjects and is as close as the touch of a hand. 

Very interesting information has been obtained from Dr. 
Battigelli's studies, and I think in our studies of pollutant 
gases, for example, that we ought to pay more attention to the 
possibility of using that difficult-to-control, more worrisome 
kind of subject, the individual with well-established chronic 
disease. 

DR. BATTIGELLI: Because you conduct experiments within a 
controlled laboratory setting, you can easily defend your activi¬ 
ties by demonstrating that the subjects you expose are immensely 
safer than other subjects who are exposed to the same variable in 
a less controlled situation. 

With regard to the variety and characteristics of exposure 
subjects, one should include the ill and impaired. There is no 
question that the impaired individual is quite often, if not 
always, a very sensitive responder. I am sure that your protocols 
have included exposure of individuals with significant disorders 
because such people are, perhaps, more sensitive to the various 
factors you wish to study. 

DR. PENGELLY: Earlier, someone asked about the meaning of a 
5% decrement in vital capacity. Vital capacity is a measurement 
of pulmonary function, and it is well known that it decreases with 
age. After growth stops, vital capacity drops approximately 0.5% 
per year. If one's vital capacity declines 5% over a two-hour 
period, that is comparable to ten years of aging. Even though the 
vital capacity may return to its original level, I think this 
suggests that age is an important factor to consider when we 
decide what we should measure and how people respond. 

It is well known, for example, that cigarette smoking produces 
a vital capacity decrement that is greater than the normal decrement 
associated with age. If exposure to some toxic material causes a 
decrement in excess of the known decrement, I think that is a suf¬ 
ficient argument to say that although this person may still have, 
functionally, enough vital capacity to get on with life, the fact 
that he will deteriorate at a more rapid rate than he would other¬ 
wise is a significant point. 


214 


Knowing the effects of cigarette smoking on pulmonary function, 
knowing that the cigarette causes 60% of all cancer mortality, how 
can we justify the question of sensitivity to air pollutants in 
the face of such an enormous known stress to the lungs? 

DR. FRANK: I would like to respond to this, not with respect 
to cigarette smoking, but with respect to vital capacity. We 
could be dealing with substances X, Y, and Z—call them pollutants 
for the moment and we could administer each of them to a care¬ 
fully controlled group in which we know the subjects' previous 
diets and all the factors that may influence their functional 
response. 

To measure vital capacity, we expose the subjects to pol¬ 
lutants X, Y, and Z for 10 minutes. Each person shows a 5% re¬ 
duction. At this stage, there is no way of weighing the im¬ 
portance of the changes in vital capacity. We are not yet in a 
position to judge the relative significance of the reductions in 
vital capacity. So, we expand the experiment; we may also use 
information obtained from the subjects while seeking answers to 
other experimental questions. Which of these pollutants is the 
most important? Are they all equally important, or are none of 
them important? We may find that if the subject is exposed to 
agent A for ten minutes on each of three days there will be a 
constinuous drop in vital capacity; but for agents B and C the 
subject will revert to control with repeated exposure. Perhaps 
now we are developing a reasonable hypothesis to suggest that one 
of these agents is more significant than another. 

At the same time, some other researcher develops some epidemio¬ 
logical data that either reinforces or weakens the hypothesis. 

What I am saying is that it is incumbent on us, as scientists, to 
continue to test the implications for health, if you will, of the 
observations we make. We cannot just say that, because an effect 
has been noted, we have to accept the effect as significant for 
health. 

DR. BROMBERG; I think Dr. Pengelly uses a very convenient 
calibration scale. He uses those very shallow slopes of function 
versus age, and extrapolates the data he gets in terms of life 
expectancy, and says, "Look! This curve crosses the time axis at 
100 years, and now you have put this subject, by your little 
exposure, onto a different curve, which if extrapolated, gives him 
a life expectancy of only 70 years. You have reduced his life 
expectancy by 30 years." Is that what you intended to say. Dr. 
Pengelly? 


215 


DR. PENGELLY: No, of course not. What I said was that one 
has to examine the entire context of the situation, which rein¬ 
forces what Bob Frank just said. The one little bit of infor¬ 
mation we get in the laboratory has to be fitted into the other 
pieces of known information--perhaps in part from animal experiment¬ 
ation and in part from epidemiological studies. The point of view 
one must have when looking at the response in the lab should be 
conditioned by the other information at hand. 

I certainly did not want to imply that a 10-minute exposure 
to ozone or some other agent, was going to have some effect on the 
subject. But, in order to understand what is taking place, one's 
observations must be made within the context of all the other 
observations that relate to that variable. 

DR. BROMBERG: I think most people would agree with that 
approach. That does not provide an easy answer to the question of 
what to do with that 5% decrement. When you were talking, I 
thought you were saying that the 5% decrement in vital capacity 
over two hours is the same decrement you would observe after 10 
years of aging, and that you can turn around and say to the inform¬ 
ed layman, "For you to understand what that decrease in vital 
capacity means, let me tell you that it is equivalent to 10 years 
of aging." That is very dramatic, but is it right? 

DR. PENGELLY; No, although it does give the layman, in a 
sense, a framework in which to judge things, but it is not to be 
interpreted as a value judgment for what happens. For example, if 
one routinely measured one's weight and noted a weight change of a 
few pounds over several weeks, such a change is probably not 
significant. But a consistent change of a few pounds over several 
days is well known to be significant. 

One must keep the scales of age in balance with other infor¬ 
mation. There are a lot of implications that I have not mentioned; 
many hidden messages in saying that a change of weight over a few 
days is important. Many unsaid things come into play because of 
one's other experience. I think it is important to keep the 
context in balance. 

DR. BATTIGELLI: To extend again what I believe Dr. Frank 
implied, perhaps a short-term experiment may offer us guidelines 
and help our progress on long-range experiments. Probably most 
chronic experiments can be studied better from an epidemiological 
approach because the study of so-called natural experiments cannot 
be duplicated in the laboratory by any stretch of the scientific 
imagination. The interplay between the short-term, bench-type 
laboratory test and the epidemiological investigation may provide 


216 


mutual support for both types of experiments and may sharpen 
attention on important target areas. 

DR. BROMBERG: So the lesson, then, for a specially-designed 
facility like the ERA Human Research Facility here on the campus 
of the University of North Carolina, is that isolation should be 
guarded against; the design of the experiment should take into 
account a wide range of information; and interpretations should be 
based on an attempt to integrate observations into a coherent 
picture. The development of this picture is based on animal 
experiments, on short-term human experiments, on medium-term human 
experiments, and on epidemiological studies. 

I am afraid, though that there will be great difficulties in 
interpreting the state of the art for a specific regulation that 
Congress might want to consider. But we must do our best with 
that problem, and not cave in as scientists to that demand. 

DR. HAZUCHA: There are some other implications of acute 
experiments. It is well known that only ideal systems, when they 
are stressed, will return to pre-stress conditions. A living 
organism, to which stress is applied, positively will not revert 
to pre-stress conditions. 

In an acute experiment, the difference between pre-stress and 
stress conditions may be miniscule. With regard to any of these 
tests that show a 0.10% decrement, perhaps you cannot state cate¬ 
gorically that, over a 70-year life span, there will be a reduction 
of 7% or seven years of life. But when a subject is exposed many 
times for many years, the resulting loss of vital capacity will 
certainly impair the quality of life. 

DR. BROMBERG: That all depends on our accepting your origin¬ 
al premise, which was that if every event has a permanent effect 
on the subject, the subject never returns to the pre-stress con¬ 
dition. I am not quite prepared to believe that. For example, we 
are losing 1% of our red cells every single day. They are dis¬ 
appearing, being eaten up by our reticuloendothelial system. Yet, 
our red cell mass, over long periods of time, remains quite constant 
so it is possible for steady-state mechanisms to maintain constant 
levels. I think it is possible to undergo some stress and to 
completely recover from it, and to do so again and again. 

I am not sure that either one of us can prove our points, but 
I think that the assumption you are making, which if we do accept 
it, would lead us to say, "Well, yes, we have to admit then, that 
if the same stress is repeated sufficiently often, there will be 
irreversible, gross, and progressive changes." I am not quite 
prepared to believe that. 


217 


DR. HAZUCHA. It is true that red blood cells are renewed, 
but the hemopoietic system is stressed, and the hemopoietic system 
as such will not return to the exact pre-stress condition. 

DR. BROMBERG: I am not sure about that. 

DR. HAZUCHA: Well, as you said, it is difficult to prove, 
almost impossible. 

DR. BROMBERG: I think you are addressing yourself, in a 
sense, to your own point of view about the significance of small 
changes. We have been talking around it, and we have arrived at 
different ways of looking at the significance of small changes. I 
think you have developed a way of looking at this which is satis¬ 
factory to you, but it still remains a touchy problem. When con¬ 
fronted with a specific circumstance, I suspect various people in 
this room would come up with a different interpretation of what 
small changes mean, even after all this discussion. 

DR. PENGELLY: I should like to return to Dr. Frank's comments 
about the importance of observed effects. I am reminded of a 
discussion I had with a person who supported the development of an 
airport quite close to a major city. He said that, as he under¬ 
stood it, people living close to airports adapt to airport noise 
and eventually become accustomed to it. My response to him was 
yes, there is an adaptive mechanism—it is called deafness, but I 
do not think deafness is an appropriate adaptation. 

Recent studies suggest that people who are not constantly ex¬ 
posed to ozone tend to react more to the gas than people who are 
regularly exposed to it. The implication of this argument is that 
individuals exposed to ozone are better off because they do not 
respond. I argue that the method of adaptation must be con¬ 
sidered. Deafness is an adaptation to airport noise, but deafness 
certainly is not desirable. We must take the factor of adaptation 
into account; we must make sure it is appropriate. 

DR. FRANK: At the risk of being boring or repetitious, I 
think the new legislation in TOSKA attempts to weigh a risk 
because weighing a risk is important in deciding what to do about 
it. I think it is reasonable, too, to say that our judgment of 
the importance of a risk may be subject to change. We deal always 
with \incertainty, and what may appear to be, from my point of view, 
flimsy evidence today, may be quite impressive, overwhelming 
evidence, if not proof, a month from now. 

Consequently, we have to be prepared to change our judgment. 
But I think, too, that as a society, we are compelled to make 


218 


judgments because there is no such thing as a benign environment. 

We have to weigh what it is that we recognize as being most import¬ 
ant/ and how much of an effort we should make to mitigate harmful 
stress. 

I do not see anything wrong with making judgments. I do not 
think we should just make observations and put them forth so that 
finally they become curios. I think if we have any reason to 
suspect that an observation has an implication/ then we, as scient¬ 
ists should pursue our observation and devise experiments designed 
to test its importance for health. 

Another thing that really impresses me is that the biological 
system is marvelously well constructed to adjust to change. I 
recognize there is a "price" for all adjustments/ but we do manage 
to adjust. 

A hypothesis about to be tested in animals suggests that 
total dosage may not be important for many of the pollutants we 
are concerned about. (I am not referring to mercury or lead. 

They are stored in the body and obviously have cumulative effects.) 
What is important/ however/ is the variation in dosage. If an 
animal is exposed to sulfur dioxide for "X" number of yearS/ the 
exposure will have no effect if the dosage is consistently low. 

On the other hand/ there will be measurable effects resulting from 
the same total dosage over the same period of time if the dosage 
of sulfur dioxide is varied each time the gas is administered. If 
this hypothesis proves true/ it may reveal impressive epidemio¬ 
logical evidence that we can apply to our studies of morbidity and 
mortality rates. 

If humans are exposed to sulfur dioxide more effects will be 
noticed with a dosage of 10 ppm for one minute than with 1 ppm for 
10 minutes. And I suspect you could develop an argument for 
epidemiologic data to reinforce that as well. 

DR. KNELSON: Our two ozone studies demonstrated the importance 
of variation in dosage very nicely. In both studies/ using 0.4 ppm 
for four hours (which could be expressed as 1.6 ppm of total dose) 
the effect on lung mechanics was considerably less dramatic than the 
effect of 0.6 ppm given for one hour/ which is less than half of 
the total dose in the 4 hour exposure to 0.4 ppm ozone. 

Our laboratory has also conducted dose-rate experiments/ using 
death in animals as an end point/ and we have obtained elegant data 
showing that ozone does exactly what you have described. These 
experiments show a continuum of dose-rate response/ which is the 
rate a given dose is administered. We have quantified the dose- 
rate response/ and we have found that short exposures to higher 


219 


levels of ozone are much more detrimental than long exposures. 

That does not surprise you, does it. Dr. Bromberg? 

DR. BROMBERG: No, but when you are dealing with a potentially 
noxious agent and with rate-limited disposal mechanisms, and if 
you increase the rate of delivery to some critical point, you will 
eventually see a very marked effect. A case in point is the agent 
potassium chloride. If you make a mistake by injecting 40 milli- 
equivalents of potassium chloride into a patient's vein, in a 
few minutes the patient dies from cardiac arrest because the 
circulatory mechanisms that dispose of noxious agents are too slow 
to cope with that much potassium chloride. 

It is not a surprise that if we push hard enough with a concen¬ 
trated enough dose in a short period of time, we can overcome the 
effectiveness of the body's disposal mechanisms. 

DR. KNELSON: But that is not a consistent tenet in toxicology. 
You must pay attention to what you are examining. We both know the 
dose-rate response is significant for toxic substances that the 
body's repair mechanisms cannot handle. 

On the other hand, there are toxic substances that elicit a 
compensatory response. If you administer a low dose of these sub¬ 
stances for a long period of time, the compensatory response will 
not be invoked, and the overall toxic effect will be greater than 
if you give the same dose over a short period of time and trigger 
the compensatory mechanisms. 

DR. HAAK: I would just like to pose a final question to this 
group. If we do not completely understand the mechanism of action, 
how are we going to get enough concurrence among scientists, our¬ 
selves for example, to make a scientifically sound argument before 
a court to justify the large costs incurred by setting a standard 
for a given pollutant? 

The safe limits for ozone, for example, have been exceeded 
nearly everywhere. It is going to be a great expense to apply air 
quality standards to ozone. How are standards for ozone to be 
defended? Even if we could meet in court, EPA on one side and 
industry on the other, society will be left without a conclusion. 

DR. BROMBERG: We have heard that there is no easy formula. 

It is clear that various people at this meeting have developed a 
personal approach to this difficult interface between science and 
society. They do not pretend that they have the right answer, but 
at least they have the satisfaction of knowing that they are 
involved in the issue and have some kind of approach to dealing 


220 


with it. We do not know the answers to most of the questions that 
are being posed, and I do not think we are going to know the 
answers in the very near future. All of us must live with that as 
best we can. 


221 


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Appendix 

Program Participants 


George Armstrong, M.D. 

Director, Health Effects 
Division 

Office of Health and Ecological 
Effects 

U.S. Environmental Protection 
Agency 

Office of Research and 
Development 
401 M Street, S.W. 

Washington, D.C. 20460 

David Bates, M.D. 

University of British Columbia 
Vancouver, British Columbia, 
Canada 

Mario C. Battigelli, M.D. 
Professor of Medicine 
Division of Pulmonary Medicine 
School of Medicine 
University of North Carolina 
Chapel Hill, North Carolina 27514 

Edward Bishop, M.D. 

Professor of Obstetrics and 
Gynecology 

Chairman, Committee on the 
Protection of Rights of 
Human Subjects 
School of Medicine 
University of North Carolina 
North Carolina Memorial Hospital 
Chapel Hill, North Carolina 27514 


Philip Bromberg, M.D. 

School of Medicine 
University of North Carolina 
724 Clinical Sciences Building 
(229H) 

Chapel Hill, North Carolina 27514 

Charles E. Daye, J.D. 

Associate Professor 
University of North Carolina 
School of Law 

Chapel Hill, North Carolina 27514 
Robert Frank, M.D. 

Department of Environmental Health 
University of Washington, SC-34 
Seattle, Washington 98195 

Milan Hazucha, M.D. 

Research Scientist 
Clinical Studies Division 
Health Effects Research Laboratory 
U.S. Environmental Protection 
Agency 

Environmental Research Center, 
MD-73 

Research Triangle Park, 

North Carolina 27711 

Steven Horvath, Ph.D. 

Director and Professor 
Institute of Environmental Stress 
University of California 
Santa Barbara, California 93106 


223 


John H. Knelson, M.D. 

Director 

Health Effects Research Laboratory 
(MD-73) 

U.S. Environmental Protection 
Agency 

Research Triangle Park, 

North Carolina 27711 

G. Guy Knickerbocker, Ph.D. 
Emergency Care Research Institute 
5200 Butler Pike 
Plymouth Meeting, Pennsylvania 
19462 

Morton Lippman, Ph.D. 

Department of Environmental 
Medicine 

New York University Medical 
Center 

550 First Avenue 

New York, New York 10016 

Michael V. McIntyre, J.D. 

P.O. Box 801 

Santa Monica, California 
90406 

David Otto, Ph.D. 

Research Psychologist 
Clinical Studies Division 
Health Effects Research 
Laboratory (MD-73) 

U.S. Environmental Protection 
Agency 

Research Triangle Park, 

North Carolina 27711 

L. David Pengelly, Ph.D. 

Associate Professor 
Department of Medicine 
McMaster University 
1200 Main Street West 
Hamilton, Ontario, Canada 


Russell Pimmel, Ph.D. 

Associate Professor 
Department of Medicine 
University of North Carolina 
Chapel Hill, North Carolina 27514 

Carl Shy, M.D. 

Professor of Epidemiology 
Department of Epidemiology 
University of North Carolina 
Chapel Hill, North Carolina 27514 

Harmon L. Smith, Ph.D. 

Divinity School 
Duke University 
Durham, North Carolina 27706 

Ralph Stacy, Ph.D. 

Research Scientist 
Clinical Studies Division 
Health Effects Research Laboratory 
(MD-73) 

U.S. Environmental Protection Agency 
Research Triangle Park, North Carolina 
27711 

Frank Starmer, Ph.D. 

Associate Professor of Computer 
Science and Associate Professor 
of Medicine 
P.O. Box 3181 

Duke University Medical Center 
Durham, North Carolina 27710 

Bernard E. Statland, M.D., Ph.D. 
Associate Professor 
Department of Pathology 
University of North Carolina 
North Carolina Memorial Hospital 
Chapel Hill, North Carolina 27514 

Thomas Wagner, Ph.D. 

Acting Associate Director 
Clinical Studies Division 
Health Effects Research Laboratory 
U.S. Environmental Protection Agency 
Environmental Research Center, MD-73 
Research Triangle Park, 

North Carolina 27711 


224 


TECHNICAL REPORT DATA 

(i^lcase read InUnictiom on the reverse before completing) 


1 . REPORT NO. 


2 . 


3. RECIPIENT'S ACCESS I Of^ NO. 


4. TITLE AND SUBTITLE 


5. REPORT DATE 


METHODOLOGIES AND PROTOCOLS IN CLINICAL RESEARCH 
Evaluating Environmental Effects on Man - 
Proceedings of a Symposium 


6. PERFORMING ORGANIZATION CODE 


7. AUTHOR(S) 


8. PERFORMING ORGANIZATION REPORT NO. 


9. PERFORMING ORGANIZATION NAME AND ADDRESS 

Clinical Studies Division 
Health Effects Research Laboratory 
Office of Research and Development 
Research Triangle Park, N.C. 27711 


10. PROGRAM ELEMENT NO. 


■1M6Q.1. 


11. CONTRACT/GRANT NO. 


12. SPONSORING AGENCY NAME AND ADDRESS 

Health Effects Research Laboratory 
Office of Research and Development 
U.S. Environmental Protection Agency 
Research Triangle Park. N.C. 27711 


13. TYPE OF REPORT AND PERIOD COVERED 


RTP,NC 


14. SPONSORING AGENCY CODE 

EPA 600/11 


15. SUPPLEMENTARY NOTES 


16. ABSTRACT 

The report is a proceedings of a symposium convened at Chapel Hill, North 
Carolina, October 26-28, 1977. Five major topics pertaining to the use of humans 
as experimental subjects are addressed in this volume: philosophy of clinical 
research, environmental and physical safety considerations in human exposure 
facilities, the EPA human studies programs, and special considerations and approaches 
in environmental clinical research. The first four parts consist of twelve formal 
papers covering issues such as ethical and legal considerations surrounding the 
use of human subjects, environmental controls and safeguards, and electrical 
surveillance and integrity. Following each paper is a summary of the discussion 
that took place after the paper was presented to the symposium participants. Part 
five is a panel discussion composed of four brief presentations and an exchange of 
comments among panel participants. 

The purpose of these proceedings is to help identify, through open discussion, 
the problems connected with using human subjects in clinical research. 


17. 


KEY WORDS AND DOCUMENT ANALYSIS 


a. 


DESCRIPTORS 


laboratories 
Laboratory tests 
humans 


b.IDENTIFIERS/OPEN ENDED TERMS 


c. COSATI Ficld/Group 


06 F, L 


18. DISTRIBUTION STATEMENT 

RELEASE TO PUBLIC 


19. SECURITY CLASS (This Report) 

UNCLASSIFIED 


21. NO. OF PAGES 


20. SECURITY CLASS (This page/ 

UNCLASSIFIED 


22. PRICE 


EPA Form 2220-1 (9-73) 






























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